CN1096460C - Novel substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl) butyl) benzamides useful for treatment of allergic diseases - Google Patents

Abstract

The present invention relates to novel substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamide derivatives, stereoisomers thereof, and pharmaceutically acceptable salts thereof which are useful as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel diseases, including Crohn's disease and ulcerative colitis; asthma; bronchitis; and emesis.

Description

Novel substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamides for use in the treatment of allergic diseases

The present invention relates to novel substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamide derivatives (referred to herein as compounds of formula (1) ) and their use as histamine receptor antagonists and tachykinin receptor antagonists. Such antagonists are useful in the treatment of asthma; bronchitis; enteritis, including Crohn's disease and ulcerative colitis; allergic rhinitis, including seasonal rhinitis and sinusitis; allergies;

Tachykinin receptor antagonists are known in the art, as EP0630887 discloses certain 4-aryl or heteroaryl-piperidines, EP0625509 discloses 4-alkylpiperidines, EP0515240 discloses certain 4-alkane Amino and 4-alkylamidopiperidines, EP0474561 discloses certain substituted piperidines.

The compounds of the present invention are valuable for their pharmacological activities, such as histamine receptor antagonism and tachykinin receptor antagonism. Antagonism of the histamine response can be manifested by blocking histamine receptors. Antagonism of the tachykinin response can be manifested by blocking tachykinin receptors. It is an object of the present invention to provide new and useful histamine antagonists. Another object of the present invention is to provide novel and useful tachykinin antagonists. A particular object of the invention are those compounds which exhibit both _H1 and _NK1 receptor antagonism.

Summary of the invention

The present invention provides novel substituted N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamide derivatives of the following formula

thing: in

其中R₂₀选自氢、C₁-C₄烷基和-CF₃；Ar₁是选自下列的基团：

R' is 1 to 3 substituents, each of which is independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; R" is hydrogen or a group selected from the following:

Wherein R ₂₀ is selected from hydrogen, C ₁ -C ₄ alkyl and -CF ₃ ; Ar ₁ is a group selected from the following:

in

R ₁ is 1 to 3 substituents, each of which is independently selected from hydrogen, halogen, hydroxyl, -CF ₃ , C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy;

R ₂ is 1 to 2 substituents, each of which is independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy;

_X1 and _X2 are as defined in one of parts A), B) or C):

A) X ₁ is hydrogen; X ₂ is a group selected from the group consisting of:

in

p is 1 or 2;

R ₃ is 1 to 3 substituents, each of which is independently selected from hydrogen, halogen, -CF ₃ , C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy;

R ₄ is 1 to 3 substituents, each of which is independently selected from hydrogen, halogen, -CF ₃ , C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy;

_R is hydrogen or hydroxyl; _Ar is a group selected from the group consisting of:

in

R ₆ is 1 to 3 substituents, each of which is independently selected from hydrogen, halogen, -CF ₃ , C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and -CO ₂ R ₉ , wherein R ₉ selected from hydrogen and C ₁ -C ₄ alkyl;

R ₇ is 1 to 2 substituents, each of which is independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy;

R ₈ is selected from hydrogen, -CH ₃ and -CH ₂ OH;

R ₁₀ is selected from hydrogen, C ₁ -C ₄ alkyl and benzyl;

Z is selected from hydrogen, C ₁ -C ₆ alkyl, -(CH ₂ ) _w -O-(CH ₂ ) _t -Y, -(CH ₂ ) _f A, -(CH ₂ ) _u CO ₂ R ₁₁ , - (CH ₂ ) _u C(O)NR ₁₂ R ₁₃ , -(CH ₂ ) _q C(O)(CH ₂ ) _h CH ₃ , -(CH ₂ ) _w' -O-Ar ₃ , -CH ₂ CH ₂ OCF ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ CF ₃ , -(CH ₂ ) ₂ CH=CH ₂ , -CH ₂ CH=CH ₂ , -CH ₂ CH=CHCH ₃ , -CH ₂ CH = _CHCH2CH3 , _{-CH2CH =} C _{( CH3} ) _{2 and -CH2OCH2CH2Si} ( _CH3 ) ₃

in

w is an integer from 2 to 5;

t is an integer from 1 to 3;

f is 2 or 3;

u is an integer from 1 to 4;

g is an integer from 1 to 3;

h is an integer from 0 to 3;

w' is an integer from 2 to 4;

Y is selected from hydrogen, -CF ₃ , -CH=CH ₂ , -CH=C(CH ₃ ) ₂ and -CO ₂ R ₁₄ , wherein R ₁₄ is selected from hydrogen and C ₁ -C ₄ alkyl;

A is selected from -NR ₁₅ R ₁₆ , acetylamino and morpholino, wherein R ₁₅ is selected from hydrogen and C ₁ -C ₄ alkyl and R ₁₆ is C ₁ -C ₄ alkyl;

R ₁₁ is selected from hydrogen and C ₁ -C ₄ alkyl;

R ₁₂ is selected from hydrogen, C ₁ -C ₄ alkyl and benzyl;

R ₁₃ is selected from hydrogen and C ₁ -C ₄ alkyl;

其中v是1至3的整数；R₁₇选自氢和-CO₂R₁₈，其中R₁₈选自氢和C₁-C₄烷基；B)X₁是羟基；X₂是选自下列的基团：其中p、R₃、Z和Ar₃定义如前；C)X₂是下式的基团： Ar ₃ is a group selected from the group consisting of:

wherein v is an integer from 1 to 3; R ₁₇ is selected from hydrogen and -CO ₂ R ₁₈ , wherein R ₁₈ is selected from hydrogen and C ₁ -C ₄ alkyl; B) X ₁ is hydroxyl; X ₂ is selected from Group: Wherein p, R ₃ , Z and Ar ₃ are defined as before; C)X ₂ is a group of the following formula:

Wherein R ₃ and R ₄ are as defined above; and

_X1 and _Z1 together form another bond between the carbon atoms bearing the _X1 and _Z1 groups;

Stereoisomers and pharmaceutically acceptable salts thereof.

Those of ordinary skill in the art know that the N-methyl-N-(4-(piperidin-1-yl)-2-(aryl) butyl) benzamide of formula (1) compound can be stereoisomer exist. In particular, it should be recognized that the N-methyl-N-(4-(piperidin-1-yl)-2-(aryl)butyl)benzamides of the present invention can serve as the 2-position (i.e., aryl) The attachment position of the substituent) There are stereoisomers of the butyl group. Any description in this application of compounds of formula (1) includes directed stereoisomers or mixtures of stereoisomers.

Specific stereoisomers may be prepared by stereospecific syntheses using enantiomerically pure or enantiomerically enriched starting materials. Directional stereoisomer starting materials or products may be resolved or recovered by techniques well known in the art, such as chiral solid phase chromatography, enzymatic resolution or fractional recrystallization of addition salts formed using reagents suitable for the purpose. Useful methods for the resolution and recovery of directional stereoisomers are well known in the art and described in Stereochemistry of Organic Compounds , ELEliel and SH Wilen, Wiley (1994) and Enantiomers, Racemates and Resolution , J. Jacques, A. Collet and SH Wilen, Wiley (1981).

Used in this article:

a) the term "halogen" means a fluorine atom, chlorine atom, bromine atom or iodine atom;

b) The term "C ₁ -C ₆ alkyl" refers to a branched or straight chain alkyl group containing 1-6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso Butyl, tert-butyl, pentyl, hexyl, cyclopentyl, cyclohexyl, etc.;

c) The term "C ₁ -C ₆ alkoxy" refers to a straight or branched alkoxy group containing 1-6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy , n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopentyloxy, cyclohexyloxy, etc.;

d) The symbol -C(O)- or -(O)C- refers to a carbonyl group of the following formula:

是指立体化学不确定的键；e) Symbol

means a bond of uncertain stereochemistry;

f) The term "kg" used in the examples and preparation examples refers to kilograms, "g" refers to grams, "mg" milligrams, "μg" refers to micrograms, "mol" refers to moles, "mmol" refers to millimoles, and "nmole " means nanomole, "L" means liter, "mL" or "ml" means milliliter, "μL" means microliter, "°C" means degree Celsius, " _Rf " means retention time, "mp" means melting point, "dec" means decomposition, "bp" means boiling point, "mmHg" means millimeter mercury pressure, "cm" means centimeter, "nm" means nanometer, "[α] _D ²⁰ "means the D-line optical rotation of sodium obtained in a 1 decimeter cup at 20°C, "c" means g/mL concentration, "THF" means tetrahydrofuran, "DMF" means dimethylformamide,"Saline" refers to saturated aqueous sodium chloride solution, "M" refers to moles, "mM" refers to millimoles, "μM" refers to micromoles, "nM" refers to nanomoles, and "pounds per square inch (psi) " refers to pounds per square inch, "TLC" refers to thin-layer chromatography, "HPLC" refers to high-pressure liquid chromatography, "HRMS" refers to high-resolution mass spectrometry, "μCi" refers to microcuries, and "ip" means intraperitoneal, "iv" means intravenous and "DPM" means disintegration rate per minute.

g) symbol

refers to phenyl or substituted phenyl, which should be understood as a group connected to position 1, and one or more substituents represented by R can be connected to any position of position 2, 3, 4, 5 or 6;

h) symbol

refers to pyridine, substituted pyridine, pyridyl or substituted pyridyl, it should be understood as a group that can be connected at the 2-position, 3-position or 4-position, and it should also be understood that when the group is connected at the 2-position, R represents One or more substituents of R can be connected at any position of 3, 4, 5 or 6; and when the group is connected at 3, one or more substituents represented by R can be connected at 2, 4, Any one of the 5 or 6 positions; that is, when the group is connected at the 4 position, one or more substituents represented by R can be connected at any one of the 2, 3, 5 or 6 positions;

是指噻吩基或噻吩，应理解为该基团连接于2或3位；i) Symbol

refers to thienyl or thiophene, it should be understood that the group is connected to the 2 or 3 position;

j) symbol

refers to naphthyl or substituted naphthyl, it should be understood that the group can be connected to the 1 or 2 position, and it should also be understood that when the group can be connected to the 1 position, one or more substituents represented by R can be connected to In any position of 2, 3, 4, 5, 6, 7 or 8; when the group is connected to 2, one or more substituents represented by R can be connected to 1, 3, 4, 5, Any one of 6, 7 or 8 positions;

k) The term "enantiomeric excess" or "ee" means that one enantiomer E1 is in excess in a mixture of two enantiomers E1 plus E2 such that

{(E1-E2)÷(E1+E2)}×100%=ee,

The symbol "(+)-" refers to the positive enantiomer, and "(-)-" refers to the negative enantiomer.

l) The term "C ₁ -C ₄ alkyl" refers to a saturated linear or branched chain alkyl group containing 1-4 carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl and tert-butyl;

m) The symbols -CO ₂ R and -C(O)OR refer to radicals of the formula:

n) The symbol -C(O)NRR refers to a group of the following formula:

是指呋喃基或呋喃，应理解为是连接于2或3位的基团；o) symbol

refers to furyl or furan, which should be understood as a group connected to the 2 or 3 position;

p) The term "pharmaceutically acceptable salts thereof" refers to acid addition salts or base addition salts.

"Pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic acid addition salt of the basic compound represented by formula (1) or its intermediate. Examples of inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acids; metal salts of acids such as sodium monohydrogen orthophosphate and potassium hydrogensulfate. Examples of organic acids which form suitable salts include mono-, di- or tricarboxylic acids. Examples of such acids are e.g. acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid , benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Such salts may exist in hydrated or substantially anhydrous form. The acid addition salts of such compounds are generally soluble in water and various hydrophilic organic solvents, and they generally have higher melting points than their free base compounds.

"Pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of the acidic compound represented by formula (1) or its intermediate. Examples of bases which form suitable salts include alkali or alkaline earth metal hydroxides, such as sodium, potassium, calcium, magnesium or barium; ammonia and aliphatic, cycloaliphatic or aromatic organic amines, such as methylamine, di Methylamine, trimethylamine, and picoline.

Preferred embodiments of compounds of formula (1) are given as follows:

1) compounds wherein _X is hydrogen are preferred;

的化合物是优选的；3)其中X₂是下式基团：

2) wherein X ₂ is a group of the following formula:

The compound is preferred; 3) wherein X ₂ is a group of the following formula:

Compounds wherein p is ₁ and Ar is 4-fluorophenyl, pyridin-2-yl, furan-2-yl or furan-3-yl are more preferred;

4) wherein X ₂ is a group of the following formula: The compound is preferred; 5) wherein X ₂ is a group of the following formula:

Compounds wherein Z is -( _CH2 ) _w -O-( _CH2 ) _t -Y, wherein w is 2 are preferred; compounds wherein Z is 2-ethoxyethyl are more preferred.

The present invention includes the following compound examples. It is understood that these examples include both (+)-isomers and (-)-isomers of the compounds and mixtures thereof. Listed below are representative compounds only and are not intended to limit the scope of the invention in any way:

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl)benzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl)-3,4,5-trimethoxybenzyl amides;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-fluorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-fluorophenyl)butyl)-3,4,5 - Trimethoxybenzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-difluorophenyl)butyl)benzamide ;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-difluorophenyl)butyl)-3, 4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3-chlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3-chlorophenyl)butyl)-3,4,5 - Trimethoxybenzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-chlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-chlorophenyl)butyl)-3,4,5 - Trimethoxybenzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)benzamide ;

N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)-3, 4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-methoxyphenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-methoxyphenyl)butyl)-3,4 , 5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3-methoxyphenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3-methoxyphenyl)butyl)-3,4 , 5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dimethoxyphenyl)butyl)benzene Formamide;

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dimethoxyphenyl)butyl)- 3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)-4-hydroxypiperidin-1-yl)-2-phenylbutyl base) benzamide;

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)-4-hydroxypiperidin-1-yl)-2-phenylbutyl base)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)-4-hydroxypiperidin-1-yl)-2-(4 - fluorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)-4-hydroxypiperidin-1-yl)-2-(3 , 4-dichlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-phenylbutyl)benzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-phenylbutyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(4-fluorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(4-fluorophenyl)butyl)-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(3,4-difluorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(3,4-difluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(3-chlorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(3-chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(4-chlorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(4-chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(3,4-difluorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(3,4-difluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(4-methoxyphenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(4-methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(3-methoxyphenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(3-methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(3,4-dimethoxyphenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl )-2-(3,4-dimethoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(3-(4-fluorophenoxy)propyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)- 2-phenylbutyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(3-(4-fluorophenoxy)propyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)- 2-(3-Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(3-(4-fluorophenoxy)propyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)- 2-(3,4-dichlorophenyl)butyl)-benzamide;

N-Methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl ) benzamide;

N-Methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl )-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Fluorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Fluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-difluorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-difluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Chlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Chlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Methoxyphenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Methoxyphenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dimethoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl )-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-difluorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-Dichlorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Methoxyphenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-Methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl )-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-difluorophenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dichlorophenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Methoxyphenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl ) benzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl )-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Fluorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Fluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-difluorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-difluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Chlorophenyl) butyl) benzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Chlorophenyl) butyl) benzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Methoxyphenyl) butyl) benzamide;

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dimethoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl ) benzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl )-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Fluorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Fluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-difluorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-furan-3-ylmethyl)-1H-benzisoimidazole-2-carbonyl)piperidin-1-yl)-2-(4-methoxy phenyl)butyl)-3,4,5-trimethoxybenzamide

N-methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-difluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Chlorophenyl) butyl) benzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Chlorophenyl) butyl) benzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Methoxyphenyl) butyl) benzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dimethoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl ) benzamide;

N-Methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl )-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Fluorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Fluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-difluorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-difluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Chlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Chlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dichlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Methoxyphenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Methoxyphenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dimethoxyphenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3, 4-dimethoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-oxobutyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl) benzamide;

N-Methyl-N-(4-(4-(1-(2-oxobutyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl) -3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-oxobutyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3,4 -Dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-oxobutyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4-methyl Oxyphenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-methyl-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl)benzamide;

N-methyl-N-(4-(4-(1-methyl-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3-chlorophenyl)butyl) -3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-methyl-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4-methoxyphenyl)butyl base) benzamide;

N-Methyl-N-(4-(4-(1-(3-(4-carboxyphenyl)propyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2 -(3-Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(3-(4-carboxyphenyl)propyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2 -(3,4-Dichlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(3-(4-carboxyphenyl)propyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2 -(4-methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-oxopropyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl) benzamide;

N-Methyl-N-(4-(4-(1-(2-oxopropyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl) -3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-oxopropyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3-chloro Phenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-oxopropyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3,4 -dichlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(5-methylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2 -(4-fluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(5-methylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2 -(3-Chlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(5-methylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2 -(3-Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(5-methylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2 -(4-methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(5-hydroxymethylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)- 2-phenylbutyl) benzamide;

N-methyl-N-(4-(4-(1-(5-hydroxymethylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)- 2-phenylbutyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(5-hydroxymethylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)- 2-(3-Chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(5-hydroxymethylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)- 2-(3,4-Dichlorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(5-hydroxymethylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)- 2-(3,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(4-carboxybenzyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl)benzene Formamide;

N-methyl-N-(4-(4-(1-(4-carboxybenzyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4-fluorobenzene Base) butyl) benzamide;

N-methyl-N-(4-(4-(1-(4-carboxybenzyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4-fluorobenzene Base) butyl) -3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(4-carboxybenzyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3-chlorobenzene Base) butyl) benzamide;

N-methyl-N-(4-(4-(1-(4-carboxybenzyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3,4- Dichlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(4-carboxybenzyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3,4- Dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(4-methoxycarbonylbenzyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl )-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(4-methoxycarbonylbenzyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Fluorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(4-methoxycarbonylbenzyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(3- Chlorophenyl) butyl) benzamide;

N-methyl-N-(4-(4-(1-(4-methoxycarbonylbenzyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Methoxyphenyl) butyl) benzamide;

N-Methyl-N-(4-(4-(1-(3-ethoxycarbonylpropyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-phenylbutyl ) benzamide;

N-methyl-N-(4-(4-(1-(3-ethoxycarbonylpropyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Fluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(3-ethoxycarbonylpropyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)-2-(4- Methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(morpholin-4-yl)ethyl)-1H-benzimidazole-2-carbonyl)-piperidin-1-yl)- 2-(4-Methoxyphenyl)butyl)benzamide;

N-methyl-N-(4-(4-diphenylmethylenepiperidin-1-yl)-2-phenylbutyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-diphenylmethylenepiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)-3,4,5-trimethoxy phenylbenzamide;

N-Methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl) -3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(furan-3-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4 -Dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-ethyl-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-fluorophenyl)butyl)benzene Formamide;

N-methyl-N-(4-(4-(1-propyl-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-difluorophenyl)butyl base) benzamide;

N-methyl-N-(4-(4-(1-butyl-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-difluorophenyl)butyl base)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-carboxyethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl)benzyl amides;

N-methyl-N-(4-(4-(1-(thiophen-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-fluoro Phenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(2-(dimethylamino)ethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3 -chlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(2-phenoxyethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4 -dichlorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(imidazol-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3-chloro Phenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2-(3,3-dimethylallyloxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(4-fluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-allyloxyethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl ) benzamide;

N-Methyl-N-(4-(4-(1-(2-allyloxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3 ,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-phenylbutyl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-phenylbutyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(4-fluorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(4-fluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3,4-difluorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3,4-difluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3-chlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3-chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(4-chlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(4-chlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3,4-dichlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(4-methoxyphenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(4-methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3-methoxyphenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3-methoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3,4-dimethoxyphenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3,4-dimethoxyphenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-phenylbutyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3,4-difluorophenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3,4-dichlorophenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3-methoxyphenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-phenylbutyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3,4-difluorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3,4-dichlorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine-1 -yl)-2-(3-methoxyphenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-benzene Butyl) benzamide;

N-methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-benzene Butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-difluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-Dichlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-benzene Butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-difluorophenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-Methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-Dichlorophenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-benzene Butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-Methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-difluorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-Dichlorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-benzene Butyl) benzamide;

N-methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-benzene Butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-difluorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-Dichlorophenyl)butyl)benzamide;

N-Methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-benzene Butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-Methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-difluorophenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-Methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-Dichlorophenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-benzene Butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-Methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-difluorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-Methyl-N-(4-(4-(1-(4,4,4-trifluorobutyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4-Dichlorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

N-Methyl-N-(4-(4-(1-(allyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl)benzamide;

N-methyl-N-(4-(4-(1-(allyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl)-3,4 , 5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(allyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorobenzene Base) butyl) benzamide;

N-methyl-N-(4-(4-(1-(allyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorobenzene Base) butyl) -3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(allyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorobenzene Base) butyl) -2-methoxy-5-(4H-triazol-4-yl) benzamide;

N-methyl-N-(4-(4-(1-(allyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorobenzene Base) butyl) -2-methoxy-5-(1H-tetrazol-1-yl) benzamide;

N-Methyl-N-(4-(4-(1-(but-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl base) benzamide;

N-Methyl-N-(4-(4-(1-(but-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl base)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(but-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3 , 4-dichlorophenyl) butyl) benzamide;

N-Methyl-N-(4-(4-(1-(but-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3 ,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-Methyl-N-(4-(4-(1-(but-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3 , 4-dichlorophenyl) butyl) -2-methoxy-5-(4H-triazol-4-yl) benzamide;

N-Methyl-N-(4-(4-(1-(but-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3 , 4-dichlorophenyl) butyl) -2-methoxy-5-(1H-tetrazol-1-yl) benzamide;

N-methyl-N-(4-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)- 2-phenylbutyl) benzamide;

N-methyl-N-(4-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)- 2-phenylbutyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)- 2-(3,4-Dichlorophenyl)butyl)benzamide;

N-methyl-N-(4-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)- 2-(3,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide;

N-methyl-N-(4-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)- 2-(3,4-dichlorophenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide;

N-methyl-N-(4-(4-(1-(3-methylbut-2-en-1-yl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)- 2-(3,4-dichlorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide;

A general synthetic method for the preparation of these compounds of formula (1) is shown in Reaction Scheme A. Reagents and starting materials are readily available to those of ordinary skill in the art. In Reaction Scheme A, unless otherwise stated, all substituents are as previously defined. Reaction Scheme A

In step 1 in Reaction Scheme A, the hydroxyl group of a suitable alcohol of formula 2 can be converted into a suitable leaving group to give a compound of formula 2a. A suitable alcohol of formula 2 is a compound wherein the stereochemistry is as required in the final product of formula (1), and R', R", and Ar are also as required in the final product of formula (1). Alternatively, formula 2 A suitable alcohol may be a compound whose stereochemistry is resolved to give the desired stereochemistry in the final product of formula (1), and R', R", and Ar are also as required in the final product of formula (1) . A suitable alcohol of formula 2 may also be a compound wherein the stereochemistry, R' and R" are as required in the final product of formula (1) and after deprotection of Ar ₁ gives the compound of formula (1) Ar _1. Alternatively, a suitable alcohol of formula 2 may also be a compound in which the resolved stereochemistry yields the desired stereochemistry in the final product of formula (1), R' and R" are as in the final product of formula (1) As required in the product, and after deprotection of Ar ₁ gives Ar ₁ as required in the final product of formula (1).

Suitable alcohols of formula 2 can be prepared using methods described herein and methods known in the art, for example U.S. Patents 5317020 and 5236921, which are incorporated herein by reference; European Patent Application 0428434 (published May 22, 1991), 0630887 ( Published Dec. 28, 1994), 0559538 (published Sept. 8, 1993); PCT Applications WO9417045 (published Aug. 4, 1994) and WO95415961 (published Jun. 15, 1995); and Bioorganic & Medicinal Chemistry Communications , 3 , 925-930 (1993).

A suitable leaving group _L1 can be displaced by a piperidine of formula 3 to give a compound of formula (1). Suitable leaving groups _L include, but are not limited to, chlorine, bromine, iodine, mesylate, tosylate, besylate, and the like. Conversion of hydroxyl groups to leaving groups such as chlorine, bromine, iodine, mesylate, tosylate, and besylate is well known in the art.

For example, compounds wherein _L1 is bromine can be formed by contacting the appropriate alcohol of formula 2 with 1.0-1.5 molar equivalents of carbon tetrabromide and 1.75 molar equivalents of triphenylphosphine. (PJ Kocienski et al., J. Org . Chem . , 42 , 353-355 (1977)). The reaction is carried out by mixing the alcohol of formula 2 with carbon tetrabromide in a suitable solvent such as dichloromethane or chloroform, followed by the addition of a solution of triphenylphosphine in a suitable solvent such as dichloromethane or chloroform. Usually, the reaction is carried out at a temperature of -10°C to room temperature. Typically, the reaction takes from 5 minutes to 24 hours. The product can be isolated and purified using techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Compounds wherein _L1 is bromine can also be formed by contacting the appropriate alcohol of formula 2 with a slight molar excess of triphenylphosphine dibromide. (RF Borch et al., J. American Chemical Society , 99 , 1612-1619 (1977)). The reaction can be carried out by contacting the appropriate alcohol of formula 2 with preformed triphenylphosphine dibromide. The reaction is carried out in a suitable solvent such as tetrahydrofuran and diethyl ether. The reaction is carried out in the presence of a suitable base, such as pyridine. Typically, the reaction is carried out at a temperature of 0°C to 50°C. Typically, the reaction takes from 5 minutes to 24 hours. The product can be isolated and purified using techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Alternatively, compounds such as wherein L ₁ is a mesylate can be formed by contacting the appropriate alcohol of formula 2 with a slight molar excess of methanesulfonyl chloride. The reaction is carried out in a suitable solvent such as dichloromethane, chloroform, toluene, benzene or pyridine. The reaction is carried out in the presence of a suitable base such as triethylamine, diisopropylethylamine or pyridine. The reaction is usually carried out at room temperature from -20°C to 50°C. Generally, the reaction takes 1 hour to 24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Compounds of formula 2a, wherein L ₁ is iodine, can be prepared from compounds of formula 2a, wherein L ₁ is mesylate, chlorine or bromine, by displacement reactions, such as the Finkelstein reaction.

For example, a compound of formula 2a, wherein L ₁ is mesylate, chlorine or bromine, is contacted with 1.0-10.0 molar equivalents of an iodine salt, such as sodium iodide or potassium iodide. The reaction is carried out in a suitable solvent such as acetone, butanone, tetrahydrofuran, tetrahydrofuran/water mixtures, toluene and acetonitrile. The reaction is usually carried out at room temperature to the reflux temperature of the solvent. Generally, the reaction takes 1-24 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In step 2 of Reaction Scheme A, the compound of formula 2a is reacted with a suitable piperidine compound of formula 3 or a salt thereof to obtain a protected compound of formula (1) or a compound of formula (1).

A suitable piperidine or salt thereof of formula 3 is wherein X _{and X} are as required in the final product of formula (1) or X _{and X} are modified or deprotected as required in the final product of formula (1) compound of. Suitable piperidines of formula 3 are well known in the art and are described in International Patent Application (PCT) WO92/06086, U.S. Patent 4908372 (March 13, 1990), U.S. Patent 4254129 (March 3, 1981), U.S. Patent 4,254,130 (March 3, 1981), US Patent 4,285,958 (April 25, 1981), US Patent 4,550,116 (October 29, 1985) and European Patent Application 0533344 (published March 24, 1993); using Analogous to these methods, prepared by suitable deprotection, protection and alkylation as known in the art in the order and number of times required to form the appropriate piperidine of formula 3. _A piperidine of formula 3 wherein X _and Z _together form another bond between the carbon atoms bearing X and _Z can be prepared by dehydrating the corresponding compound wherein X is a hydroxyl group _using conventional methods in the art Methods such as reflux in strong acid solution. Suitable piperidines of formula 3 can also be prepared by adding a readily available organometallic reagent to a suitably protected 4-piperidone or a suitably protected isonipecotic acid derivative by methods known in the art , as described in GDMaynard et al., Bioorganic and Medicinal Chemistry Communications , 3 , 753-756 (1993). Suitable piperidines of formula 3 can also be obtained from readily available starting materials or by similar methods known in the art, such as CG Wahlgren and AW Addison, Journal of Heterocyclic Chemistry , 26 , 541 (1989); R.Iemura and H.Ohtka, Medicinal Chemistry Acta Sinica, 37, 967-972 (1989); and the method described in K.Ito and G. Tsukamoto, Journal of Heterocyclic Chemistry , 24 , 31 (1987), by suitable deprotection, protection and alkane well known in the art Alkylation, prepared in the order and number of times required to form the appropriate piperidine of formula 3.

For example, contacting a compound of formula 2a with an appropriate piperidine compound of formula 3 or a salt thereof affords a protected compound of formula (1) or a compound of formula (1). The reaction is carried out in a suitable solvent such as dioxane, tetrahydrofuran, tetrahydrofuran/water mixture, acetone, acetone/water mixture, ethyl acetate, ethyl acetate/water mixture, pyridine, acetonitrile, toluene, toluene/water mixture, chlorobenzene or in dimethylformamide. The reaction is carried out in the presence of 1.0-6.0 molar equivalents of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, pyridine or diisopropylethylamine. When using the appropriate piperidine salt of formula 3, an additional molar excess of the appropriate base is used. The reaction is facilitated by adding a catalytic amount of 0.1-0.5 molar equivalent of an iodide salt such as sodium iodide, potassium iodide or tetrabutylammonium iodide. The reaction is usually carried out at room temperature to the reflux temperature of the solvent. Usually, the reaction takes 1-72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In optional step 3 of Reaction Scheme A, a compound of formula (1) or a protected compound of formula (1) wherein Z is hydrogen is modified to obtain a compound of formula (1) or a protected compound of formula (1) wherein Z is other than hydrogen ) compound. The reaction scheme A also includes optional step 3, deprotecting the protected compound of formula (1) to obtain the compound of formula (1).

Modification reactions include amide formation and alkylation of the benzimidazole nitrogen. The formation of amides from esters and acids is well known in the art. Alkylation of the benzimidazole nitrogen using a suitable alkylating agent is also well known in the art. The reaction is carried out in a suitable solvent such as dioxane, tetrahydrofuran, tetrahydrofuran/water mixtures, acetone or acetonitrile. A suitable alkylating agent is the required group Z or (CH ₂ ) _p Ar ₂ or protected Z or (CH ₂ ) _p Ar ₂ in the final product formula (1) (obtaining the final product after deprotection An alkylating agent for conversion of the required Z or (CH ₂ ) _p Ar ₂ ) in the product formula (1). The reaction is carried out in the presence of 1.0-6.0 molar equivalents of a suitable base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, triethylamine, 1,8-diazabicyclo[5.4.0 ]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide or diisopropyl ethylamine. The reaction is usually carried out at room temperature to the reflux temperature of the solvent. Generally, the reaction takes 1-72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Alternatively, a compound of formula (1) or a protected compound of formula (1) wherein Z is hydrogen and carries a benzimidazole-2-carbonyl group can be alkylated by the Mitsunobu reaction using a suitable alcohol. Suitable alcohol is that the required group _Z or (CH ₂ ) _p Ar in the final product formula (1) or protected Z or (CH ₂ ) _p Ar ₂ (obtain the final product formula ( 1) The desired Z or (CH ₂ ) _p Ar ₂ ) in the compound is converted to an alcohol.

Deprotection reactions, such as removal of hydroxyl protecting groups or hydrolysis of esters, using suitable protecting groups such as those described by T. Greene in Protecting Groups in Organic Synthesis are well known in the art.

Common synthetic methods for the preparation of alcohols of formula 2 are shown in Reaction Scheme B. Reagents and starting materials are readily available to those skilled in the art. In Scheme B, unless otherwise stated, all substituents are as previously defined. Reaction Scheme B

In step 1 of Reaction Scheme B, the appropriate protected alcohol of formula 4 is used to alkylate the appropriate nitrile of formula 5 to give the 4-(protected hydroxy)butyronitrile of formula 6.

Suitable nitriles of formula 5 are those in which _Ar1 is as desired in the final product formula (1) or where deprotection yields _Ar1 as desired in the final product formula (1). Suitable protected alcohols of formula 4 are those in which the leaving group _L2 can be replaced by an anion derived from a suitable nitrile of formula 5. Suitable leaving groups include, but are not limited to, chlorine, bromine, iodine and mesylate, with bromine and iodine being preferred. The selection and use of a suitable hydroxy protecting group _Pg1 such as those described by T. Greene in Protecting Groups in Organic Synthesis is well known in the art. In general, tetrahydropyran-2-yl and tert-butyldisilyl hydroxy protecting groups are preferred.

For example, a suitable nitrile of formula 5 is contacted with 0.8-1.2 molar equivalents of a suitable protected alcohol of formula 4 under phase transfer catalytic conditions. The reaction is carried out in the presence of a 1-10 fold molar excess of a suitable base, such as sodium hydroxide or potassium hydroxide. The reaction is carried out in a solvent such as water, ethyl acetate/water mixtures, dichloromethane/water mixtures or tetrahydrofuran/water mixtures. The reaction is carried out in the presence of a suitable phase transfer catalyst such as benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide, benzyltrimethylammonium Ammonium chloride, benzyltributylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogensulfate, and the like. The reaction is usually carried out at a temperature of -20°C to 60°C. Usually the reaction takes 1-72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Alternatively, for example, a suitable nitrile of formula 5 is contacted with 1.0-1.2 molar equivalents of a suitable protected alcohol of formula 4. The reaction is carried out in the presence of an equimolar amount of a suitable base such as sodium hydride, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium tert-butoxide, sec-butyllithium and Lithium diisopropylamide. The reaction is carried out in a solvent such as dimethylformamide or tetrahydrofuran. The reaction is usually carried out at -78°C to 0°C. The reaction usually takes 1-72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In step 2 of Reaction Scheme B, 4-(protected hydroxy)butyronitrile of formula 6 is reduced to give amino compound of formula 7.

For example, 4-(protected hydroxy)butyronitrile of formula 6 is contacted with an excess of a suitable reducing agent, such as sodium borohydride in the presence of cobalt(II) chloride; or in the presence of a suitable catalyst, such as Raney nickel or platinum oxide contact with hydrogen in the presence of For compounds of formula 6 wherein Ar ₁ is thienyl or pyridyl, sodium borohydride in the presence of cobalt(II) chloride hexahydrate is preferably employed.

When using sodium borohydride in the presence of cobalt chloride, the reaction is carried out in a suitable solvent such as methanol or ethanol. The reaction is usually carried out at a temperature of 0°C to 50°C. Usually, the reaction takes 1-72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction with aqueous acid, evaporation, trituration, chromatography and recrystallization.

When using Raney nickel, the reaction is carried out in a suitable solvent containing ammonia, such as ethanol/aqueous ammonium hydroxide or methanol/aqueous ammonium hydroxide. The reaction is usually carried out at a temperature from room temperature to 70°C. The reaction is carried out in a pressure vessel, such as a Parr hydrogenation unit, under a hydrogen pressure of 15 psig to 120 psig. The product was isolated by carefully removing the catalyst by filtration and evaporation. The product can be purified by extraction, evaporation, trituration, chromatography and recrystallization.

When platinum oxide is used, the reaction is carried out in a suitable solvent such as ethanol, methanol, chloroform, ethanol/chloroform mixtures or methanol/chloroform mixtures. The reaction is usually carried out at a temperature from room temperature to 50°C. The reaction is carried out in a pressure vessel, such as a Parr hydrogenation unit, under a hydrogen pressure of 15 psig to 120 psig. The reaction usually takes 8-48 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In step 3 of Reaction Scheme B, the amino compound of formula 7 is benzoylated with a suitable benzoylating reagent to give the benzamide of formula 8. Suitable benzoylating reagents are capable of transferring benzoyl or substituted benzoyl groups to give compounds of formula 8 benzamides, such as benzoyl halides, substituted benzoyl halides, benzoic anhydride, substituted benzoic anhydrides , mixed anhydrides of benzoic acid or mixed anhydrides of substituted benzoic acids. Suitable benzoylating reagents give benzamides of formula 8 wherein R' and R" are as required in the final product formula (1).

For example, an amino compound of formula 7 is contacted with 1-1.5 molar equivalents of a suitable benzoylating reagent. The reaction is carried out in a suitable solvent such as dichloromethane, tetrahydrofuran, acetonitrile, dimethylformamide or pyridine. The reaction is carried out in the presence of a base, such as sodium carbonate, sodium bicarbonate, triethylamine, N-methylmorpholine, diisopropylethylamine or pyridine. The reaction is usually carried out at a temperature of -20°C to 50°C. Usually, the reaction takes 1-6 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

Alternatively, for example, an amino compound of formula 7 can be reacted with 1-1.5 molar equivalents of a suitable benzoylating reagent under Schotten-Baumann conditions. The reaction is carried out in a suitable solvent such as ethyl acetate/water mixtures, acetone/water mixtures, tetrahydrofuran/water mixtures or dichloromethane/water mixtures. The reaction is carried out in the presence of a base such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate or sodium hydroxide. The reaction is usually carried out at 0°C to the reflux temperature of the solvent. Usually, the reaction takes 1-6 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In step 4 of Reaction Scheme B, the benzamide of formula 8 is methylated with a suitable methylating reagent to give the N-methylbenzamide of formula 9. A suitable methylating agent is a compound which transfers a methyl group to the benzamide of formula 8 and includes methyl iodide, methyl bromide, dimethyl sulfonate, trimethoxonium tetrafluoroborate, and the like.

For example, a benzamide of formula 8 is contacted with 1-4 molar equivalents of a suitable methylating agent. The reaction is carried out in the presence of 1-4 molar equivalents of a suitable base, such as n-butyllithium, sec-butyllithium, sodium hydride, sodium bis(trimethylsilyl)amide, potassium tert-butoxide and lithium diisopropylamide, However, sodium hydride, sodium bis(trimethylsilyl)amide and sec-butyllithium are preferred. The reaction is carried out in a solvent such as dimethylformamide or tetrahydrofuran. The reaction is usually carried out at -20°C to 60°C. Usually, the reaction takes 1-72 hours. The product can be isolated and purified by techniques well known in the art, such as extraction, evaporation, trituration, chromatography and recrystallization.

In step 5 of Reaction Scheme B, the N-methylbenzamide of formula 9 is deprotected to give the alcohol of formula 2. Deprotection reactions, such as removal of a hydroxy protecting group using a suitable protecting group, such as those described by T. Greene in Protecting Groups in Organic Synthesis, are well known in the art.

The following examples and preparations represent typical syntheses of compounds of formula (1). These examples should be understood as illustrative only and are not intended to limit the scope of the invention in any way.

Preparation Example 1

Synthesis of 4-(1H-benzimidazole-2-carbonyl)piperidine hydroiodide

Piperidine-4-carboxylic acid (500 g), water (4.2 L), tert-butanol (4 L) and 50% aqueous sodium hydroxide solution (386 g) were mixed. Di-t-butyldicarbonate (930 g) was added in portions. After 20 hours, the reaction mixture was concentrated in vacuo to about half volume. A 10% hydrochloric acid solution was slowly added until the pH was about 4. Extract with ether (3 x 4L). The organic layer was dried over magnesium sulfate, filtered and evaporated on a steam bath to about 4 L. Ethyl acetate (4L) was added and evaporated to about 4L on a steam bath. Filter and re-evaporate on a steam bath to about 2L. Cooling and filtration afforded 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid.

1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (813.7 g) was mixed with dichloromethane (6 L). Carbonyldiimidazole (633.1 g) was added in portions. After 1 hour, N-methyl-O-methylhydroxylamine hydrochloride (380.5 g) was added. After 56 hours, the reaction mixture was extracted with 5% aqueous hydrochloric acid and 5% aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give 1-(tert-butoxycarbonyl)piperidine-4-(N-methyl-O-methyl)hydroxamic acid.

Benzimidazole (57.8g, 490mmol) was mixed with dimethylformamide (570ml). Cool to about 20°C with an ice bath. Sodium hydride (20.2 g, 60% dispersion in oil, 500 mmol) was added in portions at such a rate that the temperature of the reaction mixture was maintained at about 20°C. After the sodium hydride addition was complete, it was allowed to stir for 1 hour. A solution of 2-(trimethylsilyl)ethoxymethyl chloride (60 g, 360 mmol) in dimethylformamide (60 ml) was added at such a rate that the reaction temperature was maintained below about 20°C. After 18 hours, water (50ml) was added dropwise. After the dropwise addition was complete, the reaction mixture was poured into water (2 L). The extraction was repeated with ether. The organic layers were combined and extracted with water. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give 1-((2-trimethylsilyl)ethoxymethyl)-1H-benzimidazole.

1-((2-Trimethylsilyl)ethoxymethyl)-1H-benzimidazole (91.2g, 367mmol) was mixed with tetrahydrofuran (500ml). Cool to -78°C with a dry ice/acetone bath. A solution of n-butyllithium (146 mL, 2.5M in hexane, 367 mmol) was added at a rate such that the reaction temperature remained below about -70°C. After the addition of n-butyllithium was complete, it was allowed to stir at -78°C for 30 minutes. A solution of 1-(tert-butoxycarbonyl)piperidine-4-(N-methyl-O-methyl)hydroxamic acid (99.9 g, 367 mmol) in tetrahydrofuran (100 mL) was added dropwise. Warm to room temperature. After 18 hours, saturated aqueous ammonium chloride (100 mL) was added dropwise. Water (300ml) was added and extracted with ether. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to obtain a residue. The residue was chromatographed on silica gel eluting with 10% ethyl acetate/hexanes to give a residue. The residue was recrystallized from methanol/water to give 1-(tert-butoxycarbonyl)-4-(1-((2-trimethylsilyl)ethoxymethyl)-1H-benzimidazole-2-carbonyl) piperidine.

(1-(tert-butoxycarbonyl)-4-(1-((2-trimethylsilyl)ethoxymethyl)-1H-benzimidazole-2-carbonyl)piperidine (20.0g, 43.5 mmol) was added to hydroiodic acid aqueous solution (48%, 140ml). After adding, be heated to 50 ℃. After 1.5 hours, be cooled to room temperature. After 2.5 hours, extract twice with ether. Add ether ( 300ml) and isopropanol (60ml) to obtain a solid. The solid was collected by filtration and rinsed with ether, and dried to obtain the title compound. The theoretical value of elemental analysis of C ₁₃ H ₁₅ N ₃ O·2HI: C32.19; H3.53; N8 .66; Measured value: C32.24; H3.37; N8.48.

Preparation example 2

Synthesis of 1-(tert-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine

4-(1H-benzimidazole-2-carbonyl)piperidine hydriodide (9.17g, 18.9mmol) was mixed with tert-butanol (100ml). Aqueous sodium bicarbonate solution (40ml, 1M, 40mmol) was added. Di-tert-butyl dicarbonate (5.2 g, 23.9 mmol) was added. After 72 hours, concentrate in vacuo to give a residue. The residue was mixed with ethyl acetate. Extract with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, 0.5M aqueous sodium thiosulfate and brine. The separated organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give a solid. The solid was triturated with ether and collected by filtration, recrystallized from ethyl acetate, collected and dried to give the title compound: mp 226-228°C. _Rf = 0.30 (silica gel, 20% ethyl acetate/hexane).

Preparation example 3

Synthesis of 4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine hydroiodide

1-(tert-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (2.0g, 6.1mmol), 2-(chloromethyl)pyridine (2.32g, 18.2mmol) (as follows Obtained: Mix and stir 2-(chloromethyl)pyridine hydrochloride, sodium carbonate and dichloromethane, then filter and evaporate) and potassium carbonate (4.2 g, 30.4 mmol) in acetone (40 ml) and water (10 ml) mix in. Heat to reflux. After 24 hours, cool to room temperature and dilute with ethyl acetate. Extract with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 50% ethyl acetate/hexanes afforded 1-(tert-butoxycarbonyl)-4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole- 2-Carbonyl)piperidine: melting point 45-50°C. _Rf = 0.24 (silica gel, 40% ethyl acetate/hexane). Elemental analysis theoretical value of C ₂₄ H ₂₈ N ₄ O ₃ : C68.08; H6.74; N13.23; found value: C67.88; H6.68; N13.00.

1-(tert-butoxycarbonyl)-4-(1-(piperidin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.96 g, 4.7 mmol) was mixed with dichloromethane ( 150ml) combined. Cool to 0°C with an ice bath. Hydroiodic acid (g) was added until the solution was saturated and stirred. After 30 minutes, additional hydroiodic acid (g) was added until the solution was saturated. After 2 hours, evaporate in vacuo to give the title compound after drying: mp 165-167°C.

Preparation Example 4

Synthesis of 1-(tert-butyldimethylsilyloxy)-2-bromoethane

Combine imidazole (59.5g, 880mmol), tert-butyldisilyl chloride (60.3g, 400mmol) and dimethylformamide (300ml). Cool to 0°C in an ice-salt bath. 2-Bromoethanol (50.0 g, 400 mmol) was added dropwise at such a rate that the temperature of the reaction mixture did not exceed 0°C. After 2 hours, warm to room temperature. After 18 hours, the reaction mixture was extracted three times with hexane. The hexane layers were combined and extracted three times with saturated aqueous ammonium chloride, three times with saturated aqueous sodium bicarbonate, and then with brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Preparation Example 5

Synthesis of 1-(tert-butyldimethylsilyloxy)-2-iodoethane

Prepared by the method of Preparation 4 using 2-iodoethanol to obtain the title compound.

Example 1

N-Methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- (4-fluoro Phenyl)butyl)-3,4,5-trimethoxybenzamide

1.1.1 Synthesis of 2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)butyronitrile

Using the method of Organic Synthesis Compilation, Volume VI (Org.Syn.Collective Volume VI) , 897-900 (1988), 4-fluorophenylacetonitrile (56.5g, 418mmol), 50% aqueous sodium hydroxide solution (106.3g , 1330mmol) and benzyltriethylammonium chloride (0.95g) were mixed in water (100ml). Warm to about 30°C with vigorous stirring. 1-(tert-butyldimethylsilyloxy)-2-bromoethane (50 g, 209 mmol) was added dropwise over about 30 minutes. When the dropwise addition is complete, warm to about 40°C and continue to stir vigorously. After 18 hours, the reaction mixture was diluted with ethyl acetate and stirred. After 30 minutes, the organic layer was separated and extracted three times with saturated aqueous ammonium chloride, twice with saturated aqueous sodium bicarbonate, and then with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Distillation of the residue gave the title compound: bp 100-115°C (0.2 mmHg). _Rf = 0.35 (silica gel, 1/1 dichloromethane/hexane).

1.1.2 Synthesis of 2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)butyronitrile

4-Fluorophenylacetonitrile (5.0 g, 37.0 mmol) was mixed with tetrahydrofuran (45 ml). Cool to -65°C with a dry ice/acetone bath. A solution of potassium bis(trimethylsilyl)amide (89ml, 0.5M in toluene, 44.5mmol) was added. After 1 hour, a solution of 1-(tert-butyldisiloxy)-2-iodoethane (12.7 g, 44.4 mmol) in tetrahydrofuran (10 mL) was added. Warm to room temperature after addition of 1-(tert-butyldimethylsilyloxy)-2-iodoethane. After 18 hours, the reaction mixture was diluted with THF, extracted 3 times with saturated aqueous ammonium chloride solution and 2 times with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel with 1/1 dichloromethane/hexanes gave the title compound.

1.1.3 Synthesis of 2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)butyronitrile

4-Chlorophenylacetonitrile (1.0 g, 7.4 mmol) and tetrahydrofuran (9 ml) were mixed. Cool to -70°C with a dry ice/acetone bath. A solution of potassium bis(trimethylsilyl)amide (14.8ml, 0.5M in toluene, 7.4mmol) was added. After 2 hours, the solution prepared above was added via cannula to cooled (-25°C) 1-(tert-butyldimethylsilyloxy)-2-iodoethane (2.1 g, 7.4 mmol) in THF (4 mL ) solution. After the addition of 1-(tert-butyldimethylsilyloxy)-2-iodoethane was complete, it was allowed to warm to room temperature. After 18 hours, the reaction mixture was diluted with tetrahydrofuran and extracted three times with saturated aqueous ammonium chloride, then twice with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel, eluting with 1/1 dichloromethane/hexanes, afforded the title compound.

1.1.4 Synthesis of 2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)butyronitrile 4-fluorophenylacetonitrile (1.0 g, 7.4 mmol) and tetrahydrofuran (20 ml) were mixed. Cool to -70°C with a dry ice/acetone bath. A solution of sec-butyllithium (6.3ml, 1.3M in cyclohexane, 8.1mmol) was added. After 1 hour, a solution of 1-(tert-butyldisiloxy)-2-iodoethane (2.1 g, 7.4 mmol) in tetrahydrofuran (4 mL) was added. After 2 hours, warm to room temperature. After 18 hours, the reaction mixture was combined with ethyl acetate and extracted twice with saturated aqueous ammonium chloride, then twice with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel, eluting with 1/1 dichloromethane/hexanes, afforded the title compound.

1.2 Synthesis of 2-(4-fluorophenyl)-4-(tert-butylsilyloxy)butylamine

2-(4-Fluorophenyl)-4-(tert-butyldisiloxy)butyronitrile (43.0 g, 146.5 mmol) was mixed with ethanol (200 mL) in a Parr bottle. Raney nickel (129 g) was added to the reaction mixture. Concentrated ammonium hydroxide solution (40ml) was added. Hydrogenate in a Parr shaker at 50 psig. After 24 hours, filter through a pad of celite and rinse the solids with ethanol. The filtrate was concentrated in vacuo to afford the title compound.

1.3 N-(2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)butyl)-3,4,5-trimethoxybenzyl Amide synthesis

2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)butylamine (7.33g, 24.6mmol) and sodium carbonate (2.61g, 24.6mmol) were dissolved in 4/1 ethyl acetate/ Mix in water (400ml). The reaction mixture was cooled to 0°C with an ice-salt bath. A solution of 3,4,5-trimethoxybenzoyl chloride (5.96, 25.9 mmol) in ethyl acetate (50 mL) was added slowly at such a rate that the temperature of the reaction mixture did not exceed about 5°C. After 2 hours, warm to room temperature. After 18 hours, the layers were separated, and the organic layer was extracted twice with saturated aqueous ammonium chloride, twice with saturated aqueous sodium bicarbonate, and then extracted with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting with 50% ethyl acetate/hexanes, to give, after drying, the title compound: mp 113-114°C. _Rf = 0.30 (silica gel, 50% ethyl acetate/hexane). Elemental analysis theoretical value of C ₂₆ H ₃₈ FNO ₃ Si: C63.51; H7.79; N2.85; measured value: C63.43; H7.51; N2.66.

1.4 N-methyl-N-(2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)butyl-3,4,5-trimethoxy Synthesis of phenylbenzamides

Hexane-washed sodium hydride (0.48 g, 50% in oil, 10.0 mmol) was mixed with dimethylformamide (5 mL). The reaction mixture was cooled to 0°C with an ice-salt bath. Slowly add N-(2-(4-fluorophenyl)-4-(tert-butyldimethylsiloxy)butyl-3,4,5-trimethoxybenzamide (4.0g, 8.1mmol ) in dimethylformamide (10ml). Stir until no more bubbles come out. Add iodomethane (0.62ml, 10.0mmol). After 16 hours, the reaction mixture is diluted with ethyl acetate and extracted three times with water, then with Extraction with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel eluting with 1/1 ethyl acetate/hexanes to give the title compound after drying: _Rf = 0.15 (silica gel, 1/1 ethyl acetate/hexane).Theoretical value of elemental analysis of C ₂₇ H ₄₀ FNO ₃ Si: C64.13; H7.97N2.77; measured value: C63.73; H7.90; N2. 88.

1.5 Synthesis of N-methyl-N-(2-(4-fluorophenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide

N-methyl-N-(2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)butyl-3,4,5-trimethoxybenzamide (3.9g, 7.65mmol) was combined with methanol (40ml). Ammonium fluoride (1.71g, 46.0mmol) was added. Heat to reflux. After 20 hours, concentrate in vacuo to obtain a residue. The residue was mixed with water and dichloromethane. , the aqueous layer was extracted twice with dichloromethane. The organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound: mp 30-35 °C. _{R f} =0.30 (silica gel, 10/1 ethyl acetate/methanol ).

1.6 N-methyl-N-(2-(4-fluorophenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzamide Synthesis

N-methyl-N-(2-(4-fluorophenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide (2.5g, 6.36mmol), diisopropyl Ethylamine (2.4ml, 14.0mmol) and anhydrous dichloromethane (25ml) were mixed. The reaction mixture was cooled to 0°C with an ice bath. Methanesulfonyl chloride (0.69ml, 8.9mmol) was added slowly. After 1 hour, the reaction mixture was diluted with dichloromethane and extracted three times with 1M aqueous hydrochloric acid, twice with saturated sodium bicarbonate solution, then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound: _Rf = 0.43 (silica gel, 10/1 ethyl acetate/methanol).

1.7 N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Synthesis of -2-(4-fluorophenyl)butyl)-3,4,5-trimethoxybenzamide

N-methyl-N-(2-(4-fluorophenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzamide (0.37g, 0.79mmol), diiso Propylethylamine (1.23ml, 7.1mmol) and 4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine hydriodide (0.83g, 1.2mmol ) were mixed in acetonitrile (15ml). Heat to reflux. After 18 hours, the reaction mixture was cooled, diluted with ethyl acetate, and extracted with saturated sodium bicarbonate solution, then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 10/0.3/89.7 methanol/conc. ammonia/dichloromethane gave the title compound after drying.

Preparation Example 6

Synthesis of 1-(tetrahydropyran-2-yloxy)-2-bromoethane

2-Bromoethanol (14.2ml, 200mmol) and dihydropyran (18.25ml, 200mmol) were mixed in dichloromethane (20ml). Add pyridinium p-toluenesulfonate (5 g, 20 mmol). After 2.5 hours, the reaction mixture was diluted with ether and extracted with water, 1/1 water/brine, water, then brine. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a residue. Distillation of the residue gave the title compound: bp 80-90°C (15-20 mmHg).

Example 2

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4- di Chlorophenyl)butyl)benzamide

2.1 Synthesis of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyronitrile

Sodium hydride (1.2g, 50mmol) and tetrahydrofuran (20ml) were mixed. A solution of 3,4-dichlorophenylacetonitrile (8.9 g, 47.8 mmol) in tetrahydrofuran (50 ml) was added dropwise at about 0°C. After the addition was complete, allow to warm to room temperature with stirring. After 2.5 hours, cool to 0°C and add 1-(tetrahydropyran-2-yloxy)-2-bromoethane (10.0 g, 47.9 mmol). Warm to room temperature. After 16 hours, the reaction mixture was poured into saturated ammonium chloride and extracted with ether. The organic layer was separated and extracted with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting sequentially with 5% ethyl acetate/hexane, 10% ethyl acetate/hexane, and 20% ethyl acetate/hexane gave the title compound.

2.2 Synthesis of 2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine

2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyronitrile (7 g) and ethanol (20 ml) were mixed in a Parr bottle. Raney nickel (1 g) was added to the reaction mixture. Concentrated ammonium hydroxide solution (3.5ml) was added. Hydrogenate in a Parr shaker at 50 psi. After 24 hours, filter through a pad of celite and rinse the solids with ethanol. The filtrate was concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 50% ethyl acetate/hexanes followed by 10% methanol/dichloromethane afforded the title compound.

2.3 Synthesis of N-(2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl)benzamide

2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butylamine (3.05g, 9.6mmol) and N-methylmorpholine (2.2ml, 20mmol) Mix in dry dichloromethane (25ml). The reaction mixture was cooled to 0°C with an ice-salt bath. Benzoyl chloride (1.2ml, 10.3mmol) was added slowly. After 1 hour, the reaction mixture was extracted with saturated sodium bicarbonate, then water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel, eluting sequentially with 35% ethyl acetate/hexanes and then 50% ethyl acetate/hexanes, afforded the title compound.

2.4 N-methyl-N-(2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl)benzamide synthesis

N-(2-(3,4-Dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl)benzamide (3.84g) was mixed with tetrahydrofuran (20ml). Sodium hydride (0.28 g, 11.5 mmol) was added and stirred until no more bubbling occurred. Iodomethane (1.5ml, 24.1mmol) was added. After 6 hours, the reaction mixture was diluted with ether and extracted with saturated ammonium chloride solution. The organic layer was separated and extracted with sodium bisulfite solution, water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound.

2.5 Synthesis of N-methyl-N-(2-(3,4-dichlorophenyl)-4-hydroxybutyl)benzamide

N-methyl-N-(2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl)benzamide (3.7g) and methanol (30ml) mix. Add hydrated p-toluenesulfonic acid (0.73 g) and stir. After 18 hours, concentrate in vacuo to give a residue. The residue was mixed with dichloromethane and extracted with saturated sodium bicarbonate solution, then with water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 50% ethyl acetate/hexanes followed by hexanes afforded the title compound.

2.6 Synthesis of N-methyl-N-(2-(3,4-dichlorophenyl)-4-(methylsulfonylbutyl)benzamide

N-methyl-N-(2-(3,4-dichlorophenyl)-4-hydroxybutyl)benzamide (0.5g), diisopropylethylamine (0.3ml, 1.7mmol) Mix with anhydrous dichloromethane (8ml). The reaction mixture was cooled to 0°C with an ice bath. Methanesulfonyl chloride (0.13ml, 1.7mmol) was added slowly. Warm to room temperature. After 18 hours, the reaction was quenched by adding ice. The organic layer was separated and extracted three times with 1M hydrochloric acid solution and twice with saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound.

2.7 N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- Synthesis of (3,4-dichlorophenyl)butyl)benzamide

N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)benzamide (0.6g, 1.4mmol), sodium bicarbonate (0.23g, 2.8mmol ) and 4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidine trifluoroacetate (0.63g, 1.4mmol) in tetrahydrofuran (15ml) and water (5ml) mix. Heat to reflux. After 3 days, the reaction mixture was cooled, diluted with ethyl acetate and extracted with water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 10% toluene/ethyl acetate followed by 10% ethanol/10% toluene/ethyl acetate gave, after drying, the title compound: mp 65-70°C.

2.8 N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- Synthesis of (3,4-dichlorophenyl)butyl)benzamide hydrochloride

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4- Dichlorophenyl)butyl)benzamide (0.71 g, 1.4 mmol) was mixed with methanol (10 mL). A solution of saturated hydrochloric acid in diethyl ether (3ml) was added. Evaporation in vacuo gave a residue. The residue was mixed with butanone (5ml) and diethyl ether was added slowly to give a solid. The solid was collected and dried to give the title compound.

Example 3

N-Methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)-4-hydroxypiperidin-1-yl)-2- (4 -Methoxyphenyl)butyl)benzamide

3.1 Synthesis of 2-(4-methoxyphenyl)-4-(tert-butyldimethylsilyloxy)butyronitrile

Prepared by the method of Example 1.1.1 using 4-methoxyphenylacetonitrile and 1-(tert-butyldisiloxy)-2-bromoethane to obtain the title compound.

3.2 Synthesis of 2-(4-methoxyphenyl)-4-(tert-butyldimethylsilyloxy)butylamine

Prepared by the method of Example 1.2 using 2-(4-methoxyphenyl)-4-(tert-butyldisiloxy)butyronitrile to give the title compound.

3.3 Synthesis of N-(2-(4-methoxyphenyl)-4-(tert-butyldimethylsilyloxy)butyl)benzamide become

Prepared by the method of Example 1.3 using 2-(4-methoxyphenyl)-4-(tert-butyldisiloxy)butylamine and benzoyl chloride to give the title compound.

3.4 N-methyl-N-(2-(4-methoxyphenyl)-4-(tert-butyldisiloxy)butyl)benzoyl Amine Synthesis

Prepared by the method of Example 1.4 using N-2-(4-methoxyphenyl)-4-(tert-butyldisiloxy)butyl)benzamide to obtain the title compound.

3.5 Synthesis of N-methyl-N-(2-(4-methoxyphenyl)-4-hydroxybutyl)benzamide

Prepared by the method of Example 1.5 using N-methyl-N-2-(4-methoxyphenyl)-4-(tert-butyldisiloxy)butyl)benzamide to obtain the title compound .

3.6 Synthesis of N-methyl-N-(2-(4-methoxyphenyl)-4-methylsulfonylbutyl)benzamide

Prepared by the method of Example 1.6 using N-methyl-N-2-(4-methoxyphenyl)-4-hydroxybutyl)benzamide and methanesulfonyl chloride to give the title compound.

3.7 N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)-4-hydroxypiperidine-1- Synthesis of )-2-(4-methoxyphenyl)butyl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(4-methoxyphenyl)-4-methanesulfonylbutyl)benzamide and 4-(1-(4-fluorobenzyl) (yl)-1H-benzimidazol-2-yl)-4-hydroxypiperidine to afford the title compound.

Preparation Example 7

Synthesis of 4-(1-(2-(5-hydroxymethylfuran-2-ylmethyl)-4-(1H-benzimidazole-2-carbonyl)piperidine

Hexane-washed sodium hydride (20 mmol) and tetrahydrofuran (40 ml) were mixed according to the method of P.G. McDougal et al., J. Org. Chem., 51, 3388-3390 (1986). 2,5-furandimethanol (20 mmol) was added slowly. After the bubbling stopped, tert-butyldisilyl chloride (20 mmol) was added and stirred vigorously. After about 1 hour, the reaction mixture was poured into ether and extracted with saturated aqueous sodium carbonate, water, then brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give 5-(tert-butyldisiloxy)methyl-2-hydroxymethylfuran.

1-(tert-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (10mmol), 5-(tert-butylsilyloxy)methyl-2-hydroxymethylfuran (10mmol) and triphenylphosphine (10mmol) were mixed in tetrahydrofuran (100ml). Diethyl azodicarboxylate (10 mmol) was added. After 18 hours, the reaction mixture was evaporated in vacuo to give a residue. The residue was partitioned between ethyl acetate and water. The organic layer was separated and extracted with water and brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give a residue. Chromatography of the residue on silica gel afforded 1-(tert-butoxycarbonyl)-4-(1-(5-(tert-butyldimethylsilyloxy)methylfuran-2-ylmethyl)-1H-benzo imidazole-2-carbonyl)piperidine.

1-(tert-butoxycarbonyl)-4-(1-(5-(tert-butyldimethylsilyloxy)methylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piper Pyridine (7mmol) and methanol (40ml) were mixed. Ammonium fluoride (42 mmol) was added. Heat to reflux. After 20 hours, concentrate in vacuo to give a residue. The residue was combined with water and dichloromethane. The layers were separated and the aqueous layer was extracted twice with dichloromethane, the organic layers were combined and dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(tert-butoxycarbonyl)-4-(1-(5-hydroxymethylfuran-2 -ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine.

1-(tert-butoxycarbonyl)-4-(1-(5-hydroxymethylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (5 mmol) and dioxane ( 25ml) mixed. A solution of hydrochloric acid in dioxane (1.25ml, 4M, 5mmol) was added slowly. After 45 minutes, diethyl ether was added and evaporated in vacuo to give a residue. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated and extracted with brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Example 4

N-methyl-N-(4-(4-(1-(5-hydroxymethylfuran-2-ylmethyl)-1H-benzimidazole)-4-hydroxypiperidin -1-yl)-2 -Phenylbutyl)benzamide

4.1 N-methyl-N-(4-(4-(1-(5-hydroxymethylfuran-2-ylmethyl)-1H-benzimidazole)-4-hydroxy Synthesis of piperidin-1-yl)-2-phenylbutyl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzamide and 4-(1-(5-hydroxymethylfuran-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine to afford the title compound.

Example 5

N-methyl-N-(4-(4-(benzothiazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl) benzamide

5.1 N-methyl-N-(4-(4-(benzothiazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl) Synthesis of benzamide

Using the method of Example 2.7, using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)benzamide and 4-(benzothiazole-2- carbonyl)piperidine to afford the title compound.

Example 6

N-methyl-N-(4-(4-(hydroxydiphenylmethyl)piperidin-1-yl)-2-phenylbutyl)benzamide

6.1 Synthesis of 2-phenyl-4-(tert-butyldimethylsilyloxy)butyronitrile

Prepared by the method of Example 1.1.1 using phenylacetonitrile and 1-(tert-butyldimethylsilyloxy)-2-bromoethane to obtain the title compound.

6.2 Synthesis of 2-phenyl-4-(tert-butyldimethylsilyloxy)butylamine

Prepared by the method of Example 1.2 using 2-phenyl-4-(tert-butyldisiloxy)butyronitrile to obtain the title compound.

6.3 Synthesis of N-(2-phenyl-4-(tert-butyldimethylsilyloxy)butyl)benzamide

Prepared by the method of Example 1.3 using 2-phenyl-4-(tert-butyldisiloxy)butylamine and benzoyl chloride to give the title compound.

6.4 Synthesis of N-methyl-N-(2-phenyl-4-(tert-butyldimethylsilyloxy)butyl)benzamide

Prepared by the method of Example 1.4 using N-2-phenyl-4-(tert-butyldimethylsilyloxy)butyl)benzamide to give the title compound.

6.5 Synthesis of N-methyl-N-(2-phenyl-4-hydroxybutyl)benzamide

Prepared by the method of Example 1.5 using N-methyl-N-2-phenyl-4-(tert-butyldisiloxy)butyl)benzamide to obtain the title compound.

6.6 Synthesis of N-methyl-N-(2-phenyl-4-methylsulfonylbutyl)benzamide

Prepared by the method of Example 1.6 using N-methyl-N-2-phenyl-4-hydroxybutyl)benzamide and methanesulfonyl chloride to give the title compound.

6.7 N-methyl-N-(4-(4-hydroxydiphenylmethyl)piperidin-1-yl)-2-phenylbutyl)benzamide synthesis

Prepared by the method of Example 1.7 using N-methyl-N-(2-phenyl-4-methanesulfonylbutyl)benzamide and 4-(hydroxydiphenylmethyl)piperidine to give the title compound .

Example 7

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4- di Methoxyphenyl)butyl)benzamide

7.1 Synthesis of 2-(3,4-dimethoxyphenyl)-4-(tert-butyldimethylsilyloxy)butyronitrile

Prepared by the method of Example 1.1.1 using 3,4-dimethoxyphenylacetonitrile and 1-(tert-butyldimethylsilyloxy)-2-bromoethane to obtain the title compound.

7.2 Synthesis of 2-(3,4-dimethoxyphenyl)-4-(tert-butyldisiloxy)butylamine

Prepared by the method of Example 1.2 using 2-(3,4-dimethoxyphenyl)-4-(tert-butyldisiloxy)butyronitrile to obtain the title compound.

7.3 N-(2-(3,4-dimethoxyphenyl)-4-(tert-butyldisiloxy)butyl)benzamide synthesis

Prepared by the method of Example 1.3 using 2-(3,4-dimethoxyphenyl)-4-(tert-butyldisiloxy)butylamine and benzoyl chloride to give the title compound.

7.4 N-methyl-N-(2-(3,4-dimethoxyphenyl)-4-(tert-butyldisiloxy)butyl)benzene Synthesis of formamide

Prepared by the method of Example 1.4 using N-2-(3,4-dimethoxyphenyl)-4-(tert-butyldisiloxy)butyl)benzamide to obtain the title compound.

7.5 Synthesis of N-methyl-N-(2-(3,4-dimethoxyphenyl)-4-hydroxybutyl)benzamide

Using the method of Example 1.5, using N-methyl-N-2-(3,4-dimethoxyphenyl)-4-(tert-butyldisiloxy)butyl)benzamide to prepare, The title compound was obtained.

7.6 Synthesis of N-methyl-N-(2-(3,4-dimethoxyphenyl)-4-methylsulfonylbutyl)benzamide

Prepared by the method of Example 1.6 using N-methyl-N-2-(3,4-dimethoxyphenyl)-4-hydroxybutyl)benzamide and methanesulfonyl chloride to give the title compound.

7.7 N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- Synthesis of (3,4-dimethoxyphenyl)butyl)benzamide

Adopt the method of embodiment 1.7, use N-methyl-N-(2-(3,4-dimethoxyphenyl)-4-methanesulfonylbutyl) benzamide and 4-(1-(4 -Fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.

Example 8

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(benzo[ 1, 3] Dioxolan-5-yl) butyl) benzamide

8.1 Synthesis of 2-(benzo[1,3]oxolane-5-yl)-4-(tert-butyldisiloxy)butyronitrile

Using the method of Example 1.1.1, prepared using benzo[1,3]oxolan-5-ylacetonitrile and 1-(tert-butyldimethylsilyloxy)-2-bromoethane, the title compound was obtained .

8.2 Synthesis of 2-(benzo[1,3]oxolan-5-yl)-4-(tert-butyldisiloxy)butylamine

Prepared by the method of Example 1.2 using 2-(benzo[1,3]oxolan-5-yl)-4-(tert-butyldisiloxy)butyronitrile to give the title compound.

8.3 N-(2-(Benzo[1,3]oxolan-5-yl)-4-(tert-butyldisiloxy)butyl)benzene Amide synthesis

Using the method of Example 1.3, using 2-(benzo[1,3]oxolane-5-yl)-4-(tert-butyldimethylsilyloxy)butylamine and benzoyl chloride to prepare, to obtain title compound.

8.4 N-methyl-N-(2-(benzo[1,3]oxolan-5-yl)-4-(tert-butyldisiloxy)butyl base) synthesis of benzamide

Using the method of Example 1.4, using N-2-(benzo[1,3]oxolane-5-yl)-4-(tert-butyldisiloxy)butyl)benzamide to prepare, The title compound was obtained.

8.5 Synthesis of N-methyl-N-(2-(benzo[1,3]oxolan-5-yl)-4-hydroxybutyl)benzamide

Using the method of Example 1.5, using N-methyl-N-2-(benzo[1,3]oxolane-5-yl)-4-(tert-butyldisiloxy)butyl) Benzamide preparation affords the title compound.

8.6 N-methyl-N-(2-(benzo[1,3]oxolan-5-yl)-4-methylsulfonylbutyl)benzamide Synthesis

Using the method of Example 1.6, it was prepared using N-methyl-N-2-(benzo[1,3]oxolan-5-yl)-4-hydroxybutyl)benzamide and methanesulfonyl chloride, The title compound was obtained.

8.7 N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- Synthesis of (Benzo[1,3]m-oxolan-5-yl)butyl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(benzo[1,3]oxolane-5-yl)-4-methylsulfonylbutyl)benzamide and 4- Preparation of (1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidine to afford the title compound.

Example 9

N-Methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(naphthalene-2- yl ) butyl) benzamide

9.1 Synthesis of 2-(naphthalene-2-yl)-4-(tert-butyldimethylsilyloxy)butyronitrile

Prepared by the method of Example 1.1.1 using naphthalene-2-ylacetonitrile and 1-(tert-butyldisiloxy)-2-bromoethane to obtain the title compound.

9.2 Synthesis of 2-(naphthalene-2-yl)-4-(tert-butyldimethylsilyloxy)butylamine

Prepared by the method of Example 1.2 using 2-(naphthalen-2-yl)-4-(tert-butyldisiloxy)butyronitrile to give the title compound.

9.3 Synthesis of N-(2-(naphthalene-2-yl)-4-(tert-butyldimethylsilyloxy)butyl)benzamide

Prepared by the method of Example 1.3 using 2-(naphthalen-2-yl)-4-(tert-butyldisiloxy)butylamine and benzoyl chloride to give the title compound.

9.4 Synthesis of N-methyl-N-(2-(naphthalene-2-yl)-4-(tert-butyldimethylsilyloxy)butyl)benzamide become

Prepared by the method of Example 1.4 using N-2-(naphthalen-2-yl)-4-(tert-butyldisiloxy)butyl)benzamide to give the title compound.

9.5 Synthesis of N-methyl-N-(2-(naphthalene-2-yl)-4-hydroxybutyl)benzamide

Prepared by the method of Example 1.5 using N-methyl-N-2-(naphthalen-2-yl)-4-(tert-butyldisiloxy)butyl)benzamide to give the title compound.

9.6 Synthesis of N-methyl-N-(2-(naphthalene-2-yl)-4-methylsulfonylbutyl)benzamide

Prepared by the method of Example 1.6 using N-methyl-N-2-(naphthalen-2-yl)-4-hydroxybutyl)benzamide and methanesulfonyl chloride to give the title compound.

9.7 N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- Synthesis of (naphthalene-2-yl)butyl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(naphthalene-2-yl)-4-methanesulfonylbutyl)benzamide and 4-(1-(4-fluorobenzyl) -1H-benzimidazole-2-carbonyl)piperidine to give the title compound.

Example 10

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4- di Chlorophenyl)butyl)-3,5-bis(trifluoromethyl)benzamide

10.1 N-(2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butyl)-3,5-bis(trifluoromethyl) base) synthesis of benzamide

Using the method of Example 1.3, using 2-(3,4-dichlorophenyl)-4-(tert-butylsilyloxy)butylamine and 3,5-bis(trifluoromethyl)benzylamine Acid chloride preparation afforded the title compound.

10.2 N-methyl-N-(2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butyl)-3,5-di Synthesis of (trifluoromethyl)benzamide

Using the method of Example 1.4, using N-2-(3,4-dichlorophenyl)-4-(tert-butylsilyloxy)butyl)-3,5-bis(trifluoromethyl) Benzamide preparation affords the title compound.

10.3 N-methyl-N-(2-(3,4-dichlorophenyl)-4-hydroxybutyl)-3,5-bis(trifluoromethyl)benzamide Synthesis

Using the method of Example 1.5, using N-methyl-N-2-(3,4-dichlorophenyl)-4-(tert-butylsilyloxy)butyl)-3,5-bis( trifluoromethyl)benzamide to give the title compound.

10.4 N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)-3,5-bis(trifluoromethyl)benzene Synthesis of formamide

Adopt the method for embodiment 1.6, use N-methyl-N-2-(3,4-dichlorophenyl)-4-hydroxybutyl)-3,5-bis(trifluoromethyl)benzamide and Methanesulfonyl chloride preparation afforded the title compound.

10.5 N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- Synthesis of (3,4-dichlorophenyl)butyl)-3,5-bis(trifluoromethyl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl)-3,5-bis(trifluoromethyl)benzene Preparation from formamide and 4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidine affords the title compound.

Example 11

N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3-tri Fluoromethylphenyl)butyl)-3,4,5-trimethoxybenzamide

11.1 Synthesis of 2-(3-trifluoromethylphenyl)-4-(tert-butyldimethylsilyloxy)butyronitrile

Prepared by the method of Example 1.1.1 using 3-trifluoromethylphenylacetonitrile and 1-(tert-butyldisiloxy)-2-bromoethane to obtain the title compound.

11.2 Synthesis of 2-(3-trifluoromethylphenyl)-4-(tert-butyldimethylsilyloxy)butylamine

Prepared by the method of Example 1.2 using 2-(3-trifluoromethylphenyl)-4-(tert-butyldisiloxy)butyronitrile to give the title compound.

11.3 N-(2-(3-trifluoromethylphenyl)-4-(tert-butyldisiloxy)butyl)-3,4,5-trimethyl Synthesis of Oxybenzamide

Using the method of Example 1.3, using 2-(3-trifluoromethylphenyl)-4-(tert-butyldisiloxy)butylamine and 3,4,5-trimethoxybenzoyl chloride to prepare , to give the title compound.

11.4 N-methyl-N-(2-(3-trifluoromethylphenyl)-4-(tert-butyldisiloxy)butyl)- Synthesis of 3,4,5-trimethoxybenzamide

Using the method of Example 1.4, using N-2-(3-trifluoromethylphenyl)-4-(tert-butylsilyloxy)butyl)-3,4,5-trimethoxybenzyl Amide preparation affords the title compound.

11.5 N-methyl-N-(2-(3-trifluoromethylphenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzoyl Amine Synthesis

Using the method of Example 1.5, using N-methyl-N-2-(3-trifluoromethylphenyl)-4-(tert-butyldisiloxy)butyl)-3,4,5- Trimethoxybenzamide preparation afforded the title compound.

11.6 N-methyl-N-(2-(3-trifluoromethylphenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxy Synthesis of benzamide

Using the method of Example 1.6, using N-methyl-N-2-(3-trifluoromethylphenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide, the title compound.

11.7 N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Synthesis of -2-(3-trifluoromethylphenyl)butyl)-3,4,5-trimethoxybenzamide

Using the method of Example 1.7, using N-methyl-N-(2-(3-trifluoromethylphenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzamide and 4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine hydriodide to give the title compound.

Example 12

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(thiophen-2- yl )Butyl)-3,4,5-trimethoxybenzamide

12.1 Synthesis of 2-(thiophen-2-yl)-4-(tert-butyldimethylsilyloxy)butyronitrile

Prepared by the method of Example 1.1.1 using thiophen-2-ylacetonitrile and 1-(tert-butyldisiloxy)-2-bromoethane to obtain the title compound.

12.2 Synthesis of 2-(thiophen-2-yl)-4-(tert-butyldimethylsilyloxy)butylamine

2-(thiophen-2-yl)-4-(tert-butyldimethylsilyloxy)butyronitrile (3.24mmol) and cobalt(II) chloride hexahydrate (1.54g, 6.48mmol) in methanol (50ml) mix in. While keeping the reaction temperature not exceeding 20°C using an ice bath, sodium borohydride (2.17 g, 57 mmol) was added in portions. After the addition was complete, the reaction mixture was allowed to stand at room temperature for 18 hours. The reaction mixture was evaporated in vacuo to give a residue. The residue was partitioned between dichloromethane and saturated aqueous ammonium chloride. The pH of the aqueous layer was adjusted to about 8 using 1M aqueous hydrochloric acid. Separate the layers and extract the aqueous layer several times with dichloromethane, combine the organic phases, dry over sodium sulfate, filter and concentrate in vacuo to give the title compound.

12.3 N-(2-(thiophen-2-yl)-4-(tert-butyldisiloxy)butyl)-3,4,5-trimethoxybenzene Synthesis of formamide

Prepared by the method of Example 1.3 using 2-(thiophen-2-yl)-4-(tert-butyldisiloxy)butylamine and 3,4,5-trimethoxybenzoyl chloride, the title compound.

12.4 N-methyl-N-(2-(thiophen-2-yl)-4-(tert-butyldisiloxy)butyl)-3,4,5-tri Synthesis of Methoxybenzamide

Using the method of Example 1.4, using N-2-(thiophen-2-yl)-4-(tert-butyldimethylsilyloxy)butyl)-3,4,5-trimethoxybenzamide to prepare, The title compound was obtained.

12.5 Synthesis of N-methyl-N-(2-(thiophen-2-yl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide become

Using the method of Example 1.5, using N-methyl-N-2-(thiophen-2-yl)-4-(tert-butyldisiloxy)butyl)-3,4,5-trimethoxy The benzamide preparation afforded the title compound.

12.6 N-methyl-N-(2-(thiophen-2-yl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzoyl Amine Synthesis

Using the method of Example 1.6, using N-methyl-N-2-(thiophen-2-yl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide and methanesulfonyl chloride to prepare, The title compound was obtained.

12.7 N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- Synthesis of (thiophen-2-yl)butyl)-3,4,5-trimethoxybenzamide

Using the method of Example 1.7, using N-methyl-N-(2-(thiophen-2-yl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzamide and 4- Preparation of (1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidine to afford the title compound.

Example 13

N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(pyridin- 3-yl )Butyl)-3,4,5-trimethoxybenzamide

13.1 Synthesis of 2-(pyridin-3-yl)-4-(tert-butyldimethylsilyloxy)butyronitrile

Prepared by the method of Example 1.1.2 using pyridin-3-ylacetonitrile and 1-(tert-butyldisiloxy)-2-bromoethane to obtain the title compound.

13.2 Synthesis of 2-(pyridin-3-yl)-4-(tert-butyldimethylsilyloxy)butylamine

Prepared by the method of Example 12.2 using 2-(pyridin-3-yl)-4-(tert-butyldisiloxy)butyronitrile to give the title compound.

13.3 Synthesis of N-(2-(pyridin-3-yl)-4-(tert-butyldimethylsilyloxy)butyl)-3,4,5-trimethoxybenzamide

Prepared by the method of Example 1.3 using 2-(pyridin-3-yl)-4-(tert-butyldisiloxy)butylamine and 3,4,5-trimethoxybenzoyl chloride, the title compound.

13.4 N-methyl-N-(2-(pyridin-3-yl)-4-(tert-butyldimethylsilyloxy)butyl)-3,4,5-tri Synthesis of Methoxybenzamide

Using the method of Example 1.4, using N-2-(pyridin-3-yl)-4-(tert-butyldimethylsilyloxy)butyl)-3,4,5-trimethoxybenzamide to prepare, The title compound was obtained.

13.5 Synthesis of N-methyl-N-(2-(pyridin-3-yl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide become

Using the method of Example 1.5, using N-methyl-N-2-(pyridin-3-yl)-4-(tert-butyldisiloxy)butyl)-3,4,5-trimethoxy Benzamide preparation affords the title compound.

13.6 N-methyl-N-(2-(pyridin-3-yl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzoyl Amine Synthesis

Using the method of Example 1.6, using N-methyl-N-2-(pyridin-3-yl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide and methanesulfonyl chloride to prepare, The title compound was isolated by extraction with saturated sodium bicarbonate solution.

13.7 N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- Synthesis of (pyridin-3-yl)butyl)-3,4,5-trimethoxybenzamide

Using the method of Example 1.7, using N-methyl-N-(2-(pyridin-3-yl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzamide and 4- Preparation of (1-(4-fluorobenzyl)-1H-benzimidazole-2-carbonyl)piperidine to afford the title compound.

Example 14

N-Methyl-N-(4-(4-(4-Dibenzylidenepiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl) benzamide

14.1 N-methyl-N-(4-(4-(4-diphenylmethylenepiperidin-1-yl)-2-(3,4-dichlorophenyl)butyl) benzamide

Adopt the method of embodiment 2.7, use N-methyl-N-(2-(3,4-dichlorophenyl)-4-methanesulfonylbutyl) benzamide and 4-dibenzylidene piperidine Preparation gave the title compound.

Example 15

N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl) butyl )-3, 4,5-Trimethoxybenzamide

15.1 N-(2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butyl)-3,4,5-trimethoxy Synthesis of phenylbenzamides

Using the method of Example 1.3, using 2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butylamine and 3,4,5-trimethoxybenzoyl chloride to prepare , to give the title compound.

15.2 N-methyl-N-(2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butyl)-3,4,5- Synthesis of Trimethoxybenzamide

Using the method of Example 1.4, using N-2-(3,4-dichlorophenyl)-4-(tert-butylsilyloxy)butyl)-3,4,5-trimethoxybenzyl Amide preparation affords the title compound.

15.3 N-methyl-N-(2-(3,4-dichlorophenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide synthesis

Using the method of Example 1.5, using N-methyl-N-2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butyl)-3,4,5- Trimethoxybenzamide preparation afforded the title compound.

15.4 N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzyl Amide synthesis

Using the method of Example 1.6, using N-methyl-N-2-(3,4-dichlorophenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide and methanesulfonate Acid chloride preparation afforded the title compound.

15.5 N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl) butyl)-3 , the synthesis of 4,5-trimethoxybenzamide

Using the method of Example 1.7, using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodide to give the title compound.

Example 16

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl) butyl )benzamide

16.1 N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl) Synthesis of Butyl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)benzamide and 4-(1H-benzimidazole- 2-Carbonyl)piperidine hydriodide preparation to afford the title compound.

Example 17

N-Methyl-N-(4-(4-(1-(2-(morpholin-4-yl)ethyl)-1H-benzimidazole-2-carbonyl)piperidin-1- yl)-2 -(3,4-Dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide

17.1 N-Methyl-N-(4-(4-(1-(2-(morpholin-4-yl)ethyl)-1H-benzimidazole-2-carbonyl)piperidine- Synthesis of 1-yl)-2-(3,4-dichlorophenyl)butyl)-3,4,5-trimethoxybenzamide

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)-3 , 4,5-trimethoxybenzamide (0.70mmol) and 4-(2-chloroethyl)morpholine hydrochloride (0.84mmol) and potassium carbonate (3.36mmol) in acetone (10ml), water (4ml ) and dichloromethane (5ml). Heat to reflux. After 20 hours, cooled to room temperature, the reaction mixture was concentrated in vacuo and diluted with ethyl acetate. Extract with saturated aqueous ammonium chloride, water, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound.

Example 18

N-methyl-N-(4-(4-(1-(3-ethoxycarbonylpropyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- (3,4 -Dichlorophenyl)butyl)benzamide

18.1 N-methyl-N-(4-(4-(1-(3-ethoxycarbonylpropyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Synthesis of -2-(3,4-dichlorophenyl)butyl)benzamide

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)benzyl Amide (1.35mmol), ethyl 4-bromobutyrate (5.4mmol) and potassium carbonate (2.24g, 16.2mmol) were mixed in 13/1 acetone/water (25ml). Heat to reflux. After 38 hours, cool to room temperature and dilute with ethyl acetate. Extract with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound.

Example 19

N-methyl-N-(4-(4-(1-(4-methoxycarbonylbenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4 -Dichlorophenyl)butyl)benzamide

19.1 N-methyl-N-(4-(4-(1-(4-methoxycarbonylbenzyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Synthesis of -2-(3,4-dichlorophenyl)butyl)benzamide

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)benzyl Amide (1.69mmol), methyl (4-bromomethyl)benzoate (1.55g, 6.76mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.06g, 13.52 mmol) were mixed in acetonitrile (20ml). Heat to reflux. After 72 hours, the reaction mixture was diluted with ethyl acetate and extracted with saturated aqueous ammonium chloride, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound.

Example 20

N-methyl-N-(4-(4-(1-(4-carboxybenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- (3,4-di Chlorophenyl)butyl)benzamide

20.1 N-methyl-N-(4-(4-(1-(4-carboxybenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)- Synthesis of 2-(3,4-dichlorophenyl)butyl)benzamide

N-methyl-N-(4-(4-(1-(4-methoxycarbonylbenzyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3, 4-Dichloropropyl)butyl)benzamide (0.92mmol) and lithium hydroxide hydrate (0.12g, 2.75mmol) were mixed in 4/1 tetrahydrofuran/water (45ml). After 72 hours, the reaction mixture was diluted with water and evaporated in vacuo to remove most of the THF. Acidify to pH 2 with 1M hydrochloric acid solution. Extract three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound.

Example 21

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- (3,4 -Dichlorophenyl)butyl)benzamide

21.1 N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Synthesis of -2-(3,4-dichlorophenyl)butyl)benzamide

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichloropropyl)butyl)benzyl Amide (1.36mmol), 2-chloroethyl ethyl ether (0.59g, 5.44mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.66g, 10.9mmol) in Acetonitrile (16ml) was mixed. Heat to reflux. After 18 hours, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. Extract with saturated aqueous ammonium chloride solution, 5% aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound.

Preparation example 8

Synthesis of 4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine

1-(tert-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.16mmol), furfuryl alcohol (0.10ml, 1.16mmol) and triphenylphosphine (0.33g, 1.28mmol) in Tetrahydrofuran (5ml) was mixed. Diethyl azodicarboxylate (0.20ml, 1.28mmol) was added. After 18 hours, the reaction mixture was evaporated in vacuo to give a residue. The residue was partitioned between ethyl acetate and water. The organic layer was separated and extracted with water and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound. Chromatography of the residue on silica gel eluting with 5% acetone/dichloromethane afforded 1-(tert-butoxycarbonyl)-4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2 -carbonyl)piperidine.

1-(tert-butoxycarbonyl)-4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0 mmol) and dichloromethane (5 ml) were cooled. A cooled solution of trifluoroacetic acid (1 mmol) in dichloromethane (2 ml) was added slowly. After 15 minutes, the reaction mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was separated and extracted with brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Example 22

N-Methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piper-1-yl)-2- phenylbutyl)benzene Formamide

22.1 N-methyl-N-(4-(4-(1-(furan-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Synthesis of (yl)-2-phenylbutyl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-phenyl-4-methylsulfonylbutyl)benzamide and 4-(1-(furan-2-ylmethyl)-1H- Preparation from benzimidazole-2-carbonyl)piperidine to afford the title compound.

Preparation Example 9

Synthesis of 4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine

Furfuryl alcohol (1 ml, 11.6 mmol) and tetrahydrofuran (20 ml) were mixed. Sodium hydride (0.57 g, 60% in oil, 14 mmol) was added in portions. When gas evolution ceased, ethyl bromoacetate (1.33ml, 11.7mmol) was added. Heat to reflux. After 2.5 hours, cool to room temperature. After 18 hours, the reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted twice with ethyl acetate. The organic layers were combined and extracted with saturated aqueous sodium chloride, dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 1% ethyl acetate/dichloromethane afforded ethyl furan-2-ylmethoxyacetate: R _f =0.62 (silica gel, 5% ethyl acetate/dichloromethane) .

Ethyl 2-furan-2-ylmethoxyacetate (1.2 g, 6.5 mmol) was mixed with tetrahydrofuran (10 ml). Cool in an ice bath. Lithium aluminum hydride solution (8.0 mL, 1.0 M in THF, 8.0 mmol) was added dropwise. After 2 hours, water (0.3ml) was added, 15% sodium hydroxide solution (0.3ml) was added, and water (0.9ml) was added. Stir vigorously. After 15 minutes, the reaction mixture was filtered, and the filtrate was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 2% ethyl acetate/dichloromethane afforded furan-2-ylmethyl 2-hydroxyethyl ether: R _f =0.22 (silica gel, 5% acetone/dichloromethane) .

1-(tert-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.71g, 5.2mmol), furan-2-ylmethyl 2-hydroxyethyl ether (0.74g, 5.2mmol) and triphenylphosphine (1.67g, 6.4mmol) were mixed in tetrahydrofuran (20ml). Diethyl azodicarboxylate (1.0 mL, 6.35 mmol) was added. After 21 hours, the reaction mixture was evaporated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 5% acetone/dichloromethane afforded 1-(tert-butoxycarbonyl)-4-(1-(2-furan-2-ylmethoxyethyl)-1H- Benzimidazole-2-carbonyl)piperidine: _Rf = 0.30 (silica gel, 5% acetone/dichloromethane).

1-(tert-butoxycarbonyl)-4-(1-(2-furan-2-ylmethoxyethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0mmol) and dioxane (10ml) mixed. Cool in an ice bath. A solution of hydrogen chloride in dioxane (0.25ml, 4M, 1.0mmol) was added slowly. After 45 minutes, the reaction mixture was diluted with dichloromethane and extracted with saturated aqueous sodium bicarbonate. The organic layer was separated and extracted with brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Example 23

N-methyl-N-(4-(4-(1-(2-(furan-2-ylmethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidin -1-yl) -2-Phenylbutyl)benzamide

23.1 N-methyl-N-(4-(4-(1-(furan-2-ylmethoxy)-1H-benzimidazole-2-carbonyl)piperidine- Synthesis of 1-yl)-2-phenylbutyl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-phenyl-4-methylsulfonylbutyl)benzamide and 4-(1-(2-(furan-2-ylmethoxy) )ethyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.

Preparation Example 10

Synthesis of 4-(1-(2-allyloxyethyl)-1H-benzimidazole-2-carbonyl)piperidine

Allyl hydroxyethyl ether (1.02g, 10mmol), diisopropylethylamine (4.0ml, 23mmol) and dichloromethane (20ml) were mixed. Cool in an ice bath. Methanesulfonyl chloride (1.0ml, 13mmol) was added dropwise. After 1.5 hours, the reaction mixture was extracted with 1M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give allylmethanesulfonylethyl ether: _Rf = 0.80 (silica gel, 20% ethyl acetate/dichloromethane).

1-(tert-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine (1.87g, 5.68mmol), allylmethylsulfonyl ethyl ether (1.83g, 10.1mmol) and Potassium carbonate (1.60g.11.5mmol) was mixed in acetone (21ml) and water (7ml). Heat to reflux. After 18 hours, the reaction mixture was concentrated in vacuo to remove most of the acetone. The concentrated reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were extracted with saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 15% ethyl acetate/dichloromethane afforded 1-(tert-butoxycarbonyl)-4-(1-(2-allyloxyethyl)-1H-benzo Imidazole-2-carbonyl)piperidine: _Rf = 0.48 (silica gel, 20% ethyl acetate/dichloromethane).

Mix 1-(tert-butoxycarbonyl)-4-(1-(2-allyloxyethyl)-1H-benzimidazole-2-carbonyl)piperidine (1.0mmol) and dioxane (3ml) . A solution of hydrochloric acid in dioxane (4ml, 4M, 16mmol) was added. After 30 minutes, the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated and extracted with saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give the title compound.

Example 24

N-Methyl-N-(4-(4-(1-(2-allyloxyethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- phenylbutyl ) benzamide

24.1 N-methyl-N-(4-(4-(1-(2-allyloxyethyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Synthesis of (yl)-2-phenylbutyl)benzamide

Adopt the method of embodiment 1.7, use N-methyl-N-(2-phenyl-4-methanesulfonylbutyl) benzamide and 4-(1-(2-(2-allyloxyethyl) )-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.

Preparation Example 11

Synthesis of 4-(1-(2-(3,3-dimethylallyloxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine

Prepared by the method of Preparation Example 10 using 3-methyl-2-butene hydroxyethyl ether.

Example 25

N-methyl-N-(4-(4-(1-(2-(3,3-dimethylallyloxy)ethyl)-1H-benzimidazole-2-carbonyl) piperidine-1 -yl)-2-phenylbutyl)benzamide

25.1 N-methyl-N-(4-(4-(1-(2-(3,3-dimethylallyloxy)ethyl)-1H-benzimidazole-2- Synthesis of Carbonyl)piperidin-1-yl)-2-phenylbutyl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-phenyl-4-methylsulfonylbutyl)benzamide and 4-(1-(2-(3,3-dimethylene Propoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine to give the title compound.

Example 26

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3-chlorophenyl)butyl) -3,4,5 - Trimethoxybenzamide

26.1 Synthesis of 2-(3-chlorophenyl)-4-(tert-butyldimethylsilyloxy)butyronitrile

Prepared by the method of Example 1.1.1 using 3-chlorophenylacetonitrile and 1-(tert-butyldimethylsilyloxy)-2-bromoethane to obtain the title compound.

26.2 Synthesis of 2-(3-chlorophenyl)-4-(tert-butyldimethylsilyloxy)butylamine

Prepared by the method of Example 1.2 using 2-(3-chlorophenyl)-4-(tert-butyldisiloxy)butyronitrile to give the title compound.

26.3 N-(2-(3-chlorophenyl)-4-(tert-butyldimethylsilyloxy)butyl)-3,4,5-trimethoxybenzene Synthesis of formamide

Prepared by the method of Example 1.3 using 2-(3-chlorophenyl)-4-(tert-butyldisiloxy)butylamine and 3,4,5-trimethoxybenzoyl chloride, the title compound.

26.4 N-methyl-N-(2-(3-chlorophenyl)-4-(tert-butyldimethylsilyloxy)butyl)-3,4,5-trimethyl Synthesis of Oxybenzamide

Using the method of Example 1.4, using N-2-(3-chlorophenyl)-4-(tert-butyldisiloxy)butyl)-3,4,5-trimethoxybenzamide to prepare, The title compound was obtained.

26.5 Synthesis of N-methyl-N-(2-(3-chlorophenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide become

Using the method of Example 1.5, using N-methyl-N-2-(3-chlorophenyl)-4-(tert-butyldisiloxy)butyl)-3,4,5-trimethoxy Benzamide preparation affords the title compound.

26.6 N-methyl-N-(2-(3-chlorophenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzoyl Amine Synthesis

The title compound was obtained by the method of Example 1.6 using N-methyl-N-2-(3-chlorophenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide.

26.7 N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3-chlorophenyl)butyl base)-3,4,5-trimethoxybenzamide synthesis

Using the method of Example 1.7, using N-methyl-N-(2-(3-chlorophenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzamide and 4- Preparation of (1H-benzimidazole-2-carbonyl)piperidine hydriodide to afford the title compound.

Example 27

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3-chloro Phenyl)butyl)-3,4,5-trimethoxybenzamide

27.1 N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Synthesis of -2-(3-chlorophenyl)butyl)-3,4,5-trimethoxybenzamide

Using the method of Example 21.1, using N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3-chlorophenyl)butyl base)-3,4,5-trimethoxybenzamide and 2-chloroethyl ethyl ether to give the title compound.

Example 28

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-chlorophenyl)butyl) -3,4,5 - Trimethoxybenzamide

28.1 Synthesis of 2-(4-chlorophenyl)-4-(tert-butyldimethylsilyloxy)butyronitrile

Prepared by the method of Example 1.1.1 using 4-chlorophenylacetonitrile and 1-(tert-butyldimethylsilyloxy)-2-bromoethane to obtain the title compound.

28.2 Synthesis of 2-(4-chlorophenyl)-4-(tert-butyldimethylsilyloxy)butylamine

Prepared by the method of Example 1.2 using 2-(4-chlorophenyl)-4-(tert-butyldisiloxy)butyronitrile to give the title compound.

28.3 N-(2-(4-chlorophenyl)-4-(tert-butyldimethylsilyloxy)butyl)-3,4,5-trimethoxybenzene Synthesis of formamide

Prepared by the method of Example 1.3 using 2-(4-chlorophenyl)-4-(tert-butyldisiloxy)butylamine and 3,4,5-trimethoxybenzoyl chloride, the title compound.

28.4 N-methyl-N-(2-(4-chlorophenyl)-4-(tert-butyldimethylsilyloxy)butyl)-3,4,5-trimethyl Synthesis of Oxybenzamide

Using the method of Example 1.4, using N-2-(4-chlorophenyl)-4-(tert-butyldisiloxy)butyl)-3,4,5-trimethoxybenzamide to prepare, The title compound was obtained.

28.5 Synthesis of N-methyl-N-(2-(4-chlorophenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide become

Using the method of Example 1.5, using N-methyl-N-2-(4-chlorophenyl)-4-(tert-butylsilyloxy) butyl)-3,4,5-trimethoxy Benzamide preparation affords the title compound.

28.6 N-methyl-N-(2-(4-chlorophenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzoyl Amine Synthesis

Following the method of Example 1.6, using N-methyl-N-2-(4-chlorophenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide, the title compound was obtained.

28.7 N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-chlorophenyl)butyl base)-3,4,5-trimethoxybenzamide synthesis

Using the method of Example 1.7, using N-methyl-N-(2-(4-chlorophenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzamide and 4- Preparation of (1H-benzimidazole-2-carbonyl)piperidine hydriodide to afford the title compound.

Example 29

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 4-chloro Phenyl)butyl)-3,4,5-trimethoxybenzamide

29.1 N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Synthesis of -2-(4-chlorophenyl)butyl)-3,4,5-trimethoxybenzamide

Using the method of Example 21.1, using N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-chlorophenyl)butyl base)-3,4,5-trimethoxybenzamide and 2-chloroethyl ethyl ether to give the title compound.

Example 30

N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dimethylphenyl) butyl)-3 , 4,5-trimethoxybenzamide

30.1 Synthesis of 2-(3,4-dimethylphenyl)-4-(tert-butyldisiloxy)butyronitrile

Prepared by the method of Example 1.1.1 using 3,4-dimethylphenylacetonitrile and 1-(tert-butyldisiloxy)-2-bromoethane to obtain the title compound.

30.2 Synthesis of 2-(3,4-dimethylphenyl)-4-(tert-butyldisiloxy)butylamine

Prepared by the method of Example 1.2 using 2-(3,4-dimethylphenyl)-4-(tert-butyldisiloxy)butyronitrile to obtain the title compound.

30.3 N-(2-(3,4-dimethylphenyl)-4-(tert-butyldisiloxy)butyl)-3,4,5-trimethyl Synthesis of Oxybenzamide

Using the method of Example 1.3, using 2-(3,4-dimethylphenyl)-4-(tert-butyldisiloxy)butylamine and 3,4,5-trimethoxybenzoyl chloride Preparation gave the title compound.

30.4 N-methyl-N-(2-(3,4-dimethylphenyl)-4-(tert-butyldisiloxy)butyl)- Synthesis of 3,4,5-trimethoxybenzamide

Using the method of Example 1.4, using N-2-(3,4-dimethylphenyl)-4-(tert-butylsilyloxy)butyl)-3,4,5-trimethoxybenzene Formamide preparation afforded the title compound.

30.5 N-methyl-N-(2-(3,4-dimethylphenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide Synthesis

Using the method of Example 1.5, using N-methyl-N-2-(3,4-dimethylphenyl)-4-(tert-butyldisiloxy)butyl)-3,4,5 - Preparation of trimethoxybenzamide to give the title compound.

30.6 N-methyl-N-(2-(3,4-dimethylphenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzene Synthesis of formamide

Using the method of Example 1.6, using N-methyl-N-2-(3,4-dimethylphenyl)-4-hydroxybutyl)-3,4,5-trimethoxybenzamide, to obtain title compound.

30.7 N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dimethylbenzene Synthesis of (yl)butyl)-3,4,5-trimethoxybenzamide

Using the method of Example 1.7, using N-methyl-N-(2-(3,4-dimethylphenyl)-4-methylsulfonylbutyl)-3,4,5-trimethoxybenzyl Preparation of the amide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodide to afford the title compound.

Example 31

N-Methyl-N-(4-(4-(1-(imidazol-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- phenylbutyl) benzamide

31.1 N-methyl-N-(4-(4-(1-(1-benzylimidazol-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piper Synthesis of pyridin-1-yl)-2-phenylbutyl)benzamide

Using the method of Example 21.1, using N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-phenylbutyl)benzamide and Preparation of 1-benzyl-imidazol-2-ylmethyl chloride hydrochloride to afford the title compound.

31.2 N-methyl-N-(4-(4-(1-(imidazol-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Base) -2-phenylbutyl) benzamide

N-methyl-N-(4-(4-(1-(1-benzylimidazol-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2 -Phenylbutyl)benzamide (5mmol) and 10% palladium on carbon (1.5g) were mixed in methanol (50ml). Anhydrous ammonium formate (25 mmol) was added. Heat to reflux. After 18 hours, filter and rinse with dichloromethane and evaporate in vacuo to give the title compound.

Preparation Example 12

Synthesis of 4-(1-(2-ethoxyethyl)-1H-benzimidazole)-4-hydroxypiperidine

1-(2-Ethoxyethyl)-1H-benzimidazole (2.0 g, 10.51 mmol) and tetrahydrofuran (20 ml) were mixed. Cool to -78°C in a dry ice/acetone bath. Lithium diisopropylamide solution (4.62ml, 2.5M in hexane, 11.56mmol) was added dropwise. After 1 hour, a solution of 1-(tert-butoxycarbonyl)piperidin-4-one (2.09 g, 10.51 mmol) in tetrahydrofuran (10 mL) was added dropwise. Warm to room temperature over 3 hours. Water was added and the layers were separated. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 1/1 ethyl acetate/hexanes afforded 1-(tert-butoxycarbonyl)-4-(1-(2-ethoxyethyl)-1H-benzimidazole )-4-Hydroxypiperidine: _Rf = 0.25 (silica gel, 1/1 ethyl acetate/hexane).

1-(tert-butoxycarbonyl)-4-(1-(2-ethoxyethyl)-1H-benzimidazole)-4-hydroxypiperidine (2.05 g) was cooled in an ice bath. Trifluoroacetic acid (25ml) was added dropwise. After 1 hour diethyl ether (100ml) was added and evaporated in vacuo to give a residue. Dichloromethane and 5% potassium carbonate solution were added. Stir vigorously. After 3 hours, the layers were separated and the aqueous layer was extracted three times with dichloromethane. The combined organic layers were dried over potassium carbonate, filtered and evaporated in vacuo to give the title compound: _Rf = 0.18 (silica gel, 2% triethylamine/ethyl acetate).

Example 32

N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole)-4-hydroxypiperidin-1-yl)-2- phenylbutyl) benzamide

32.1 N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole)-4-hydroxypiperidine-1- Synthesis of (yl)-2-phenylbutyl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-phenyl-4-methylsulfonylbutyl)benzamide and 4-(1-(2-ethoxyethyl)-1H- Benzimidazole)-4-hydroxypiperidine to give the title compound.

Preparation Example 13

Synthesis of 2-methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride

2-Hydroxy-5-nitrobenzoic acid (21.5g, 117mmol), potassium carbonate (162.3g, 1.174mol) and iodomethane (136.8g, 96.4mmol) were mixed in acetone (500ml). Heat to reflux. After 18 hours, the reaction mixture was cooled to room temperature and iodomethane (136.8 g, 96.4 mmol) was added. Heat again to reflux. After 56 hours, the reaction mixture was cooled to room temperature and filtered, rinsed with acetone, and the filtrate was evaporated in vacuo to give a residue. The residue was recrystallized from ethanol to give a second residue. The second residue was mixed with chloroform (ca. 100ml), filtered and the filtrate evaporated in vacuo to give methyl 2-methoxy-5-nitrobenzoate. _Rf = 0.38 (silica gel, ethyl acetate/hexane 1/1).

Mix methyl 2-methoxy-5-nitrobenzoate (13.3 g, 63 mmol) and methanol. 5% palladium on carbon (0.66 g) was added. Hydrogenate in a pressure vessel at 50 psi. After 17 hours, filter through a pad of celite to remove the catalyst and evaporate the filtrate in vacuo to give a residue. The residue and dichloromethane were combined and extracted with water. The organic layer was dried over _Na2SO4 , filtered and evaporated _in vacuo to give methyl 2-methoxy-5-aminobenzoate. _Rf = 0.18 (silica gel, ethyl acetate/methanol 1/1). Elemental analysis theoretical value for C ₉ H ₁₁ NO ₃ : C, 59.66; H, 6.12; N, 7.73; found value: C, 59.44; H, 6.04; N, 7.62.

Methyl 2-methoxy-5-aminobenzoate (3.94g, 21.7mmol) and triethylorthoformate (12.8g, 86.7mmol) were mixed in glacial acetic acid (20ml). After 20 hours, the reaction mixture was concentrated in vacuo to remove ethanol. Glacial acetic acid (20ml) and sodium azide (5.64g, 86.7mmol) were added. Heat to 70°C. After 1 hour, glacial acetic acid (10ml) was added and heating was continued to 70°C. After 1 hour, the reaction mixture was cooled to room temperature and diluted with water (500ml). The solid was collected by filtration, rinsed with water and dried to give methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate.

Methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (2.86g, 12.2mmol) and 1M aqueous sodium hydroxide solution (13.43ml, 14.43mmol) were dissolved in methanol/water (100ml, 5:1 v/v). Heat to reflux. After 4 hours, concentrate in vacuo to remove most of the methanol, add water (50 mL) and adjust the pH to about 4 with 1M aqueous hydrochloric acid. Evaporate in vacuo to give a solid. Water was added to slurry the solid, filtered and dried to give 2-methoxy-5-(1H-tetrazol-1-yl)benzoic acid.

Alternatively, methyl 2-methoxy-5-(1H-tetrazol-1-yl)benzoate (13.3 g, 56.8 mmol) was mixed with methanol (150 ml). Aqueous 1M sodium hydroxide solution (62.5ml, 62.5mmol) was added. Heat to reflux. After 30 minutes, methanol (50ml) and water (50ml) were added and heating was continued to reflux. After 1 hour, the product was concentrated in vacuo to remove most of the solvent. The pH was adjusted to about 1 to 2 using 1M aqueous hydrochloric acid to give a solid. The solid was collected by filtration, washed with water, and dried to give 2-methoxy-5-(1H-tetrazol-1-ylbenzoic acid).

2-Methoxy-5-(1H-tetrazol-1-yl)benzoic acid (1.2g, 5.5mmol) and dichloromethane (40ml). Oxalyl chloride (0.72ml, 8.25mmol) was added dropwise, followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.

Example 33

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-fluorophenyl)butyl)-2- methoxy -5-(1H-tetrazol-1-yl)benzamide

33.1 N-(2-(4-fluorophenyl)-4-(tert-butylsilyloxy)butyl)-2-methoxy-5-(1H- Synthesis of tetrazol-1-yl)benzamide

2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)butylamine (5.0g, 16.8mmol) and sodium bicarbonate (7.0g, 83mmol) in acetone (50ml) and water (50ml). 2-Methoxy-5-(1H-tetrazol-1-yl)benzoyl chloride (3.3 g, 14.55 mmol) was added. After 18 hours, the reaction mixture was diluted with ethyl acetate, the layers were separated, and the organic layer was extracted with saturated aqueous sodium bicarbonate, water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a residue. The residue was chromatographed on silica gel, eluting sequentially with 50% ethyl acetate/hexane and then 75% ethyl acetate/hexane, to give the title compound after drying: R _f =0.58 (silica gel, ethyl acetate).

33.2 N-methyl-N-(2-(4-fluorophenyl)-4-(tert-butylsilyloxy)butyl)-2-methoxy-5-(1H-tetrazole-1 -Synthesis of benzamide

N-(2-(4-fluorophenyl)-4-(tert-butylsilyloxy)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzyl The amide (3.75g, 7.13mmol) was mixed in tetrahydrofuran (20ml). Cool in a dry ice/acetone bath. Sec-butyllithium (7.2ml, 1.3M in cyclohexane, 9.5mmol) was added. After 30 minutes, iodomethane (2.0 ml, 32.1 mmol) was added. The reaction mixture was warmed to room temperature, then heated to reflux. After 18 hours, cooled, the reaction mixture was diluted with ethyl acetate, extracted with saturated aqueous sodium bicarbonate, then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give a residue. Chromatography of the residue on silica gel, eluting with 3/7 ethyl acetate/hexane, gave the title compound after drying: R _f =0.63 (silica gel, ethyl acetate).

33.3 N-methyl-N-(2-(4-fluorophenyl)-4-hydroxybutyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzene Synthesis of formamide

Using the method of Example 1.5, using N-methyl-N-2-(4-fluorophenyl)-4-(tert-butyldisiloxy)butyl)-2-methoxy-5-( Preparation from 1H-tetrazol-1-yl)benzamide afforded the title compound: R _f =0.18 (silica gel, ethyl acetate).

33.4 N-methyl-N-(2-(4-fluorophenyl)-4-methylsulfonylbutyl)-2-methoxy-5-(1H-tetrazole-1- base) synthesis of benzamide

Using the method of Example 1.6, using N-methyl-N-2-(4-fluorophenyl)-4-hydroxybutyl)-2-methoxy-5-(1H-tetrazol-1-yl) benzamide to give the title compound.

33.5 N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(4-fluorophenyl)butyl Synthesis of -2-methoxy-5-(1H-tetrazol-1-yl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(4-fluorophenyl)-4-methylsulfonylbutyl)-2-methoxy-5-(1H-tetrazole-1 -yl)benzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydroiodide to give the title compound.

Example 34

N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl) butyl )-2- Methoxy-5-(1H-tetrazol-1-yl)benzamide

34.1 N-(2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butyl)-2-methoxy-5- Synthesis of (1H-tetrazol-1-yl)benzamide

Prepared by the method of Example 33.1 using 2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butylamine (5.0 g, 16.8 mmol) to give the title compound.

34.2 N-methyl-N-(2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butyl)-2-methyl Synthesis of Oxy-5-(1H-tetrazol-1-yl)benzamide

Using the method of Example 1.4, using N-(2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butyl)-2-methoxy-5-(1H -tetrazol-1-yl)benzamide to give the title compound.

34.3 N-methyl-N-(2-(3,4-dichlorophenyl)-4-hydroxybutyl)-2-methoxy-5-(1H-tetrazol-1-yl) Synthesis of benzamide

Using the method of Example 1.5, using N-methyl-N-2-(3,4-dichlorophenyl)-4-(tert-butyldisilyloxy)butyl)-2-methoxy- Preparation of 5-(1H-tetrazol-1-yl)benzamide to afford the title compound.

34.4 N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)-2-methoxy-5-(1H-tetra Synthesis of Azol-1-yl)benzamide

Using the method of Example 1.6, using N-methyl-N-2-(3,4-dichlorophenyl)-4-hydroxybutyl)-2-methoxy-5-(1H-tetrazole-1 -yl) benzamide to give the title compound.

34.5 N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl) Synthesis of Butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)-2-methoxy-5-(1H-tetra Preparation from azol-1-yl)benzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodide to afford the title compound.

Preparation Example 14

Synthesis of 2,2,2-trifluoroethyl triflate

2,2,2-Trifluoroethanol (12.4ml, 170mmol), pyridine (13.6ml, 170mmol) and dichloromethane (40ml) were mixed. Cool in an ice bath. Trifluoromethanesulfonic anhydride (50 g, 196 mmol) was added over about 45 minutes. After 15 minutes, water was added, the two layers were separated, and the organic layer was extracted with water. The organic layer was dried over magnesium sulfate, filtered and concentrated by short path distillation to give the title compound: bp 89-91°C.

Example 35

N-Methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- ( 4-fluorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide

35.1 N-methyl-N-(4-(4-(1-(2,2,2-trifluoroethyl)-1H-benzimidazole-2-carbonyl)piperidine-1- Synthesis of yl)-2-(4-fluorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide

Prepared by the method of Example 21.1 using 2,2,2-trifluoroethyl triflate to give the title compound.

Preparation Example 15

Synthesis of 4-(1-allyl-1H-benzimidazole-2-carbonyl)piperidine

Prepared by the method of Preparation 8 using allyl alcohol to obtain the title compound.

Example 36

N-methyl-N-(4-(4-(1-allyl-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl ) Butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide

36.1 N-methyl-N-(4-(4-(1-allyl-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4- Synthesis of Dichlorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)-2-methoxy-5-(1H-tetra Preparation from oxazol-1-yl)benzamide and 4-(1-allyl-1H-benzimidazole-2-carbonyl)piperidine to afford the title compound.

Preparation Example 16

Synthesis of 2-methoxy-5-(4H-triazol-4-yl)benzoyl chloride

According to the Journal of Chemical Society (J.Chem.Soc.) (C), the method of 1664 (1967), 2-methoxy-5-aminobenzoic acid methyl ester (2.0g, 11mmol), N, N-dimethyl Carboxamide azine (1.56g, 11mmol), p-toluenesulfonic acid (190mg) were mixed in toluene (25ml). The reaction vessel was fitted with a vent inlet to flush the vessel headspace with argon and scrub the exhaust with dilute aqueous hydrochloric acid. Heat to reflux. After 20 hours, the reaction mixture was concentrated in vacuo to give a residue. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with dichloromethane. The organic layers were combined, dried over magnesium sulfate, filtered and evaporated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 70% ethyl acetate/dichloromethane followed by 5% methanol/dichloromethane gave a residue. The residue was recrystallized from ethyl acetate/hexane to give methyl 2-methoxy-5-(4H-triazol-4-yl)benzoate: mp 191-195.5°C.

Alternatively, according to the method of Journal of Medicinal Chemistry (J.Med.Chem.), 21 , 1100 (1978), methyl 2-methoxy-5-aminobenzoate (1.8 g, 10 mmol), diformylhydrazine ( 0.97g, 11mmol) and phosphorus pentoxide (1.84g, 13mmol). Heat to 160°C. After 1.5 hours, the reaction mixture was cooled and saturated aqueous sodium bicarbonate was added. Extract three times with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 40% ethyl acetate/dichloromethane and then 5% methanol/dichloromethane afforded 2-methoxy-5-(4H-triazol-4-yl)benzene Methyl formate: melting point 179-182°C.

Methyl 2-methoxy-5-(4H-triazol-4-yl)benzoate (56mmol) was mixed with methanol (200ml) and water (50ml). Aqueous 1M sodium hydroxide solution (62.5ml, 62.5mmol) was added. Heat to reflux. After 8 hours, concentrate in vacuo to remove most of the solvent. The pH was adjusted to about 1-2 with 1M aqueous hydrochloric acid and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give 2-methoxy-5-(4H-triazol-4-yl)benzoic acid.

2-Methoxy-5-(4H-triazol-4-yl)benzoic acid (5mmol) and dichloromethane (40ml) were mixed. Oxalyl chloride (0.72ml, 8.25mmol) was added dropwise, followed by dimethylformamide (3 drops). After 4 hours, evaporate in vacuo and dry to give the title compound.

Example 37 N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 4- fluorophenyl )butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide

37.1 N-(2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)butyl)-2-methoxy-5-(4H-triazole- Synthesis of 4-yl)benzamide

Using the method of Example 33.1, using 2-(4-fluorophenyl)-4-(tert-butyldisiloxy)butylamine and 2-methoxy-5-(4H-triazole-4- base) benzoyl chloride to give the title compound.

37.2 N-methyl-N-(2-(4-fluorophenyl)-4-(tert-butylsilyloxy)butyl)-2-methoxy-5- Synthesis of (4H-triazol-4-yl)benzamide

Using the method of Example 1.4, using N-2-(4-fluorophenyl)-4-(tert-butylsilyloxy)butyl)-2-methoxy-5-(4H-triazole- 4-yl)benzamide to give the title compound.

37.3 N-methyl-N-(2-(4-fluorophenyl)-4-hydroxybutyl)-2-methoxy-5-(4H-triazol-4-yl)benzoyl Amine Synthesis

Using the method of Example 1.5, using N-methyl-N-2-(4-fluorophenyl)-4-(tert-butyldisiloxy)butyl)-2-methoxy-5-( 4H-triazol-4-yl)benzamide to give the title compound.

37.4 N-methyl-N-(2-(4-fluorophenyl)-4-methylsulfonylbutyl)-2-methoxy-5-(4H-triazol-4-yl) Synthesis of benzamide

Using the method of Example 1.6, using N-methyl-N-2-(4-fluorophenyl)-4-hydroxybutyl)-2-methoxy-5-(4H-triazol-4-yl) benzamide to give the title compound.

37.5 N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- Synthesis of (4-fluorophenyl)butyl)-2-methoxy-5-(4H-triazol-4-yl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(4-fluorophenyl)-4-methylsulfonylbutyl)-2-methoxy-5-(4H-triazole-4 -yl)benzamide and 4-(1-(pyridin-2-ylmethyl)-1H-benzimidazole-2-carbonyl)piperidine hydriodide to give the title compound.

Preparation Example 18 Synthesis of 2-methoxy-5-trifluoromethoxybenzoyl chloride

2-Methoxy-5-trifluoromethoxybenzene (1.0 g, 5.2 mmol) and trifluoroacetic acid (200 mL) were mixed. Hexamethylenetetramine (26 g, 185.7 mmol) was slowly added in portions. Heat at 60°C. After 24 hours, cool to room temperature and pour the reaction mixture into 2M aqueous sulfuric acid (500ml). Cool and extract 10 times with ether. The combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo to give a residue. Chromatography of the residue on silica gel, eluting with 1/4 ethyl acetate/hexanes, afforded 2-methoxy-5-trifluoromethoxybenzaldehyde.

According to the method of Heterocycyles, 16 , 2091 (1981), 2-methoxy-5-trifluoromethoxybenzaldehyde (0.58g, 2.65mmol) and 2-methylbut-2-ene ( 37ml) was mixed in tert-butanol (16ml). A solution of sodium dihydrogen phosphate hydrate (0.92 g) and sodium chloride (0.42 g, 4.7 mmol) in water (10 ml) was added dropwise. After 4 hours the pH of the reaction mixture was adjusted to 8-9 with 1M aqueous sodium hydroxide solution. The reaction mixture was evaporated near room temperature to remove most of the n-butanol. Water (40ml) was added and extracted three times with hexane (10ml). The pH of the aqueous layer was adjusted to about 1 with 1M aqueous hydrochloric acid and extracted five times with ether. The organic layers were combined, dried over sodium sulfate, filtered and evaporated in vacuo to give a residue. Chromatography of the residue on silica gel eluting with 1/1 ethyl acetate/hexanes containing 0.5% acetic acid gave 2-methoxy-5-trifluoromethoxybenzoic acid: R _f =0.34 (silica gel containing 0.5% acetic acid in 1/1 ethyl acetate/hexane).

2-Methoxy-5-trifluoromethoxybenzoic acid (0.6g, 2.53mmol) and dichloromethane (10ml) were mixed. Cool in an ice bath. Oxalyl chloride (0.64ml, 5.0mmol) was added dropwise followed by dimethylformamide (1 drop). Warm to room temperature. After 3 hours, evaporate in vacuo and dry to give the title compound.

Example 38 N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl) -2- Methoxy-5-trifluoromethoxybenzamide

38.1 N-(2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butyl)-2-methoxy-5-trifluoromethyl Synthesis of Oxybenzamide

Using the method of Example 33.1, using 2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butylamine (5.0 g, 16.8 mmol) and 2-methoxy- Preparation of 5-trifluoromethoxybenzoyl chloride to afford the title compound.

38.2 N-methyl-N-(2-(3,4-dichlorophenyl)-4-(tert-butyldisiloxy)butyl)-2-methoxy- Synthesis of 5-Trifluoromethoxybenzamide

Using the method of Example 1.4, using N-2-(3,4-dichlorophenyl)-4-(tert-butylsilyloxy)butyl)-2-methoxy-5-trifluoromethane Oxybenzamide preparation to afford the title compound.

38.3 N-methyl-N-(2-(3,4-dichlorophenyl)-4-hydroxybutyl)-2-methoxy-5-trifluoromethoxybenzoyl Amine Synthesis

Using the method of Example 1.5, using N-methyl-N-2-(3,4-dichlorophenyl)-4-(tert-butyldisilyloxy)butyl)-2-methoxy- Preparation of 5-trifluoromethoxybenzamide to afford the title compound.

38.4 N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)-2-methoxy-5-trifluoromethoxy Synthesis of benzamide

Using the method of Example 1.6, using N-methyl-N-2-(3,4-dichlorophenyl)-4-hydroxybutyl)-2-methoxy-5-trifluoromethoxybenzyl amide to give the title compound.

38.5 N-Methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl Synthesis of -2-methoxy-5-trifluoromethoxybenzamide

Using the method of Example 1.7, using N-methyl-N-(2-(3,4-dichlorophenyl)-4-methylsulfonylbutyl)-2-methoxy-5-trifluoromethoxy phenylbenzamide and 4-(1H-benzimidazole-2-carbonyl)piperidine hydriodide to afford the title compound.

Example 39 N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-( 3,4- Dichlorophenyl)butyl)-2-methoxy-5-trifluoromethoxybenzamide

39.1 N-methyl-N-(4-(4-(1-(2-ethoxyethyl)-1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2- Synthesis of (3,4-dichlorophenyl)butyl)-2-methoxy-5-trifluoromethoxybenzamide

Using the method of Example 21.1, using N-methyl-N-(4-(4-(1H-benzimidazole-2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorobenzene (1)butyl)-2-methoxy-5-trifluoromethoxybenzamide and 2-chloroethyl ethyl ether to give the title compound.

Preparation 17 Synthesis of 4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine hydroiodide

According to the method of Tet.Let., 35 , 3997-6000 (1994), 1-hydroxyl-2-tetrahydropyran-2-yloxyethane ( Chemical Society Chemical Communication Journal (J.Chem, Soc, Chem, Commun.) , 1766(1990) (5.0mmol), 1,1-diethyl azodicarboxylate (10mmol), 2,2,2-trifluoroethanol (100mmol) and tributylphosphine (10mmol) in benzene (100 mL). After 6 hours, concentrate in vacuo to give a residue. The residue is chromatographed on silica gel to give 2-tetrahydropyran-2-yloxyethyl 2,2,2-trifluoroethyl ether.

2-Tetrahydropyran-2-yloxyethylbut-2-en-1-yl ether (2mmol) and magnesium bromide (6mmol) were mixed in diethyl ether (10ml). After 24 hours, extract with water, then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to give 2-hydroxyethyl 2,2,2-trifluoroethyl ether.

Adopt the method for Preparation Example 9, use 2-hydroxyethyl 2,2,2-trifluoroethyl ether and 1-(tert-butoxycarbonyl)-4-(1H-benzimidazole-2-carbonyl)piperidine ( 2.0 g, 6.1 mmol) to give 1-(tert-butoxycarbonyl)-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2 -carbonyl)piperidine.

1-(tert-butoxycarbonyl)-4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine (5.0mmol ) and dichloromethane (150ml) were mixed. Cool to 0°C with mixing in an ice bath. Hydroiodic acid (g) was added until the solution was saturated and stirred. After 30 minutes, additional hydroiodic acid (g) was added until the solution was saturated. After 2 hours, evaporate in vacuo to give the title compound after drying.

Example 40 N-methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piper Pyridin-1- yl)-2-(4-fluorophenyl)butyl)-2-methoxy-5-(1H-tetrazole-1-)benzamide

40.1 N-Methyl-N-(4-(4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piper Synthesis of pyridin-1-yl)-2-(4-fluorophenyl)butyl)-2-methoxy-5-(1H-tetrazol-1-yl)benzamide

Using the method of Example 1.7, using N-methyl-N-(2-(4-fluorophenyl)-4-methylsulfonylbutyl)-2-methoxy-5-(1H-tetrazole-1 -yl)benzamide and 4-(1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-benzimidazole-2-carbonyl)piperidine hydriodide, The title compound was obtained.

Tachykinins are a class of neuropeptides that share a common C-terminal sequence, Phe-Xaa-Gly-Leu-Met- _NH2 . Tachykinins are widely distributed in the peripheral and central nervous systems, where they bind at least three types of receptors. Among the tachykinin receptors, _NK1 , _NK2 and _NK3 receptors are defined according to their preferential binding affinities to substance P, neurokinin A (NKA) and neurokinin B (NKB), respectively.

Tachykinin antagonists have been shown to be used in the treatment of various tachykinin-mediated diseases and indications, including: allergic reactions; unwanted immune responses; asthma; bronchitis; allergic rhinitis, including seasonal rhinitis and Sinusitis; allergy; contact dermatitis; allergic dermatitis; inflammatory bowel disease, including Crohn's disease and ulcerative colitis; and emesis.

Tachykinin-mediated diseases and indications are understood to be those diseases which are related in whole or in part to tachykinins in one or more of their clinical manifestations. Also, tachykinin-related factors are not necessarily the cause of specific tachykinin-mediated diseases and indications. Tachykinin antagonists are useful in the management or alleviation of those diseases and conditions in which tachykinins are mediated.

The present invention provides novel and useful tachykinin antagonists of formula (1) or stereoisomers or pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides a method for treating tachykinin-mediated diseases and indications with a tachykinin antagonist, comprising administering a therapeutically effective amount of a compound of formula (1) to said patient in need of such treatment , said diseases and indications include: anaphylaxis; adverse immune response; asthma; bronchitis; allergic rhinitis, including seasonal rhinitis and sinusitis; allergy; contact dermatitis; allergic dermatitis; inflammatory bowel disease diseases, including Crohn's disease and ulcerative colitis; and vomiting.

Anaphylaxis occurs when IgE antibodies react directly to nontoxic antigens such as pollen. During this response, it often results in the release of pharmacological transmitters such as histamine by IgE-sensitized mast cells in an acute inflammatory response. The characteristics of this reaction depend on the tissue in which the reaction occurs and cause allergic diseases, including: allergic rhinitis, including seasonal rhinitis and sinusitis; pulmonary diseases, such as asthma; allergic dermatitis, such as urticaria, angioedema , eczema, allergic dermatitis and contact dermatitis; gastrointestinal allergies, such as those caused by food and drugs; cramps; nausea; vomiting; diarrhea and ocular allergies.

Histamine, acting through activation of _H1 receptors, is an important transmitter of the above-mentioned reactions associated with anaphylaxis. In the acute phase of allergic rhinitis, histamine _H1 receptor antagonists have been shown to effectively suppress nasal itching, rhinorrhea and sneezing associated with this indication. However, histamine _H1 receptor antagonists are not effective in alleviating nasal congestion. The acute response to an allergen in rhinitis is often followed by a chronic inflammatory response, during which the inflamed nasal mucosa becomes hypersensitive to antigens and nonspecific stimuli. Histamine _H1 receptor antagonists are also ineffective in reducing symptoms of this chronic phase reaction.

The present invention provides novel and useful histamine antagonists of formula (1) or stereoisomers or pharmaceutically acceptable salts thereof.

In another embodiment, the present invention provides a method for the treatment of allergic diseases with histamine antagonists, comprising administering a therapeutically effective amount of a compound of formula (1) to said patient in need thereof, said diseases including allergic rhinitis , including seasonal rhinitis and sinusitis; pulmonary disease, such as asthma; allergic dermatitis, such as urticaria, angioedema, eczema, atopic dermatitis, and contact dermatitis; gastrointestinal allergies, such as those caused by food and drugs Gastrointestinal irritation; convulsions; nausea; vomiting; diarrhea and ocular allergies.

In addition to histamine, tachykinins, especially substance P, also play an important role in allergic reactions and produce certain symptoms different from histamine reactions. The occurrence of these symptoms is due to the release of tachykinins by the sensory nerves located in the trigeminal nerve area around blood vessels and lining the nasal mucosa by irritants or inflammatory transmitters such as histamine.

Patients with allergic rhinitis have been shown to have higher nasal substance P levels when they have symptoms of rhinitis (Mosimann et al., J. Allergy Clin. Immunol. 92 , 95 (1993); Takeyama et al. , Journal of Drug Pharmacology (J.Pharm.Pharmacol.), 46 , 41 (1994); and Wantanable et al., Ann.Otol.Rhinol.and Laryngol., 102 , 16 (1993). Tachykinins administered topically or intravenously induce nasal obstruction, inflammatory cell recruitment, glandular secretion, and microvascular leakage. Nasal obstruction produced by substance P was found to be _NK1 receptor mediated. Braunstein et al., Am.Rev. Respir.Dis., 144 , 630 (1991); Devillier et al., Eur.Respir.J., 1 , 356 (1988). In addition, sensory nerve-mediated effects, such as nasal irritation and allergic Sex is also the result of tachykinin release. Anggard, Acta Otolarynglo.113 , 394 (1993). After long-term capsaicin administration, the depletion of tachykinin in the nasal sensory nerve improves the patient's rhinitis symptoms. Lacroix et al., Clin.and Expert . Allergy, 21 , 595 (1991).

The antagonism of histamine on _H1 receptors can be used in the treatment of allergic diseases such as rhinitis. Likewise, antagonism of tachykinins, especially substance P, at their preferential receptors may be useful in the treatment of symptoms co-occurring with allergic diseases. Thus, a potential advantage of antagonists having affinity for both _H1 and _NK1 receptors would attenuate or prevent the clinical manifestations of allergic disease mediated by both receptors.

More specifically, the present invention provides novel and useful compounds of formula (1) or their stereoisomers or pharmaceutically acceptable salts which are both tachykinin antagonists and histamine antagonists.

In another embodiment, the present invention provides a method for treating allergic diseases with a compound that is a tachykinin antagonist and a histamine antagonist at the same time, comprising administering a therapeutically effective amount of the formula (1 ) compounds, the allergic diseases include: allergic rhinitis, including seasonal rhinitis and sinusitis; inflammatory bowel disease, including Crohn's disease and ulcerative colitis.

The various diseases and indications to be treated herein are well known to those of ordinary skill in the art. It will also be recognized that one of ordinary skill in the art can affect the associated disease by treating an ongoing disease patient with a therapeutically effective amount of a compound of formula (1) or prophylactically treating a diseased patient.

The term "patient" as used herein refers to a warm-blooded animal, such as a mammal, suffering from a specified allergic disease. Guinea pigs, dogs, cats, rats, mice, horses, cows, sheep and humans are examples of animals within the meaning of this term.

As used herein, the term "therapeutically effective amount" of a compound of formula (1) means an amount effective to control the diseases described herein. The term "control" means to slow down, intervene, inhibit or stop the whole process of the disease process described herein, and while not necessarily the complete elimination of all disease symptoms, the term also includes preventive treatment of the disease.

A therapeutically effective amount is readily determined by the diagnostician, having skill in the art, by application of conventional techniques and observations made under similar circumstances. In determining a therapeutically effective amount, the diagnostician should consider a variety of factors including, but not limited to: the species of mammal; its size, age and health; the particular disease involved; the extent of the disease involved and the severity of the disease ; the response of the individual patient; the specific compound administered; the route of administration; the bioavailability characteristics of the drug formulation; the selected dosing regimen; concomitant drugs; and other relevant circumstances.

A therapeutically effective amount of a compound of formula (1) is expected to range from 0.1 milligram per kilogram of body weight per day (mg/kg/day) to about 100 mg/kg/day. Preferred amounts are determined by those skilled in the art.

In the effective treatment of patients suffering from the above diseases, the compound of formula (1) can be administered in any form or manner that makes the effective amount of the compound bioavailable, including oral, inhalation and parenteral routes. For example, compounds of formula (1) can be administered orally, by inhalation of aerosol or dry powder, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally and topically. Oral or inhalational administration is generally preferred for the treatment of allergic diseases. Those skilled in the art of preparing medicaments can easily select the appropriate administration form and mode according to the characteristics of the selected compound, the disease or indication to be treated, the stage of the disease or indication and other relevant circumstances. (Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990)).

The compounds of the present invention may be administered alone or in the form of pharmaceutical compositions in combination with pharmaceutically acceptable carriers or excipients, the ratio and nature of which will depend on the solubility and chemical properties of the selected compound, Route of administration for sample selection and standard pharmaceutical practice. Compounds of the invention which are effective per se are also formulated or administered in the form of their pharmaceutically acceptable salts, including acid addition or base addition salts, for reasons such as stability, ease of crystallization and enhanced solubility.

In another embodiment, the present invention provides pharmaceutical compositions comprising an effective amount of a compound of formula (1) in admixture or additionally in combination with one or more pharmaceutically acceptable carriers or excipients.

Pharmaceutical compositions can be prepared in a conventional manner well known in the art of pharmacy. The carrier or excipient can be a solid, semi-solid or liquid material which acts as a vehicle or medium for the active ingredient. Suitable carriers or excipients are known in the art. The pharmaceutical composition is suitable for oral, inhalation, parenteral or topical use and can be administered to patients in the form of tablets, capsules, aerosols, inhalants, suppositories, solutions or suspensions.

The compounds of the invention can be administered orally, for example, with an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic purposes, the compounds can be incorporated with excipients and used in the form of tablets, lozenges, capsules, elixirs, suspensions, syrups, sachets, chewing gums and the like. These formulations should contain at least 4% by weight of the compound of the present invention as active ingredient, but this can vary with the particular dosage form, and will usually contain from 4% to about 70%. The amount of compound present in the composition is such that a suitable dosage will be provided. Preferred compositions and formulations of the invention can be determined by those skilled in the art.

Tablets, pills, capsules and lozenges, etc. may also contain one or more of the following auxiliary agents: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose; disintegrants such as algae Acids, Primogel, and cornstarch, among others; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweeteners such as sucrose and saccharin or flavoring agents such as peppermint, methyl salicylate, or orange essence . When the dosage unit form is a capsule, it may contain, in addition to the above materials, a liquid carrier such as polyethylene glycol or a fatty oil. Other dosage unit forms may contain other various materials which modify the dosage unit form, such as coatings. Thus, tablets or pills may be coated with sugar, shellac or other enteric coating substances. A syrup may contain, in addition to the compounds of this invention, sucrose as a sweetening agent and certain preservatives, colorings and flavors and flavors. Materials used in the preparation of the various compositions should be pharmaceutically pure and nontoxic in the amounts employed.

For parenteral therapeutic administration, the compounds of the invention may be incorporated into solutions or suspensions. These preparations should contain at least 0.1% of the compound of the invention, but the amount can also be from 0.1% to 50% by weight. The amount of compound of formula (1) in such compositions should be such that a suitable dosage will be provided. Preferred compositions and formulations can be determined by those skilled in the art.

The compounds of the invention may also be administered by inhalation, eg, in aerosol or dry powder form. The compounds of the present invention, or formulations thereof, may be administered by liquefied or compressed gas or delivered by a suitable pump system. Administration formulations for inhalation of compounds of formula (1) may be delivered in the form of monophasic, biphasic or triphasic systems. Different systems can be used for administering aerosols of compounds of formula (1) according to the invention. Dry powder formulations can be prepared by granulating or grinding the compound of formula (1) into a suitable particle size or by mixing the granulated or ground compound of formula (1) with a suitable carrier material such as lactose or the like. Inhalation delivery includes the necessary container, activator, valve, inner container, etc. Preferred aerosols and dry powders for inhalation administration can be determined by those skilled in the art.

The compounds of this invention may also be administered topically, and when topically administered, the carrier may also suitably comprise a solution, ointment or gel base. For example, the base may contain one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and ethanol, and emulsifiers and stabilizers. Topical formulations contain a compound of formula (1) or a pharmaceutically acceptable salt thereof at a concentration of about 0.1 to about 10% w/v (weight per unit volume).

The solution or suspension may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycol, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or Methyl hydroxybenzoates; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates, or phosphates and substances used to adjust osmotic pressure such as chlorine NaCl or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes, or multiple dose vials of glass or plastic.

Antagonism of [H ³ ] -mepyramine combined with histamine H ₁ receptors proposed in embodiment A

Those skilled in the art can evaluate and determine the _H1 receptor affinity of the proposed histamine antagonist in rat brain or Chinese hamster ovary cells (CHOpcDNA3H1R cells) transfected with human histamine _H1 receptor gene.

For studies in rat brains, juvenile male rats were decapitated and brains were immediately removed. Cortex was isolated and used immediately or stored at -20°C. For studies in Chinese hamster ovary cells, confluent cells were freshly scraped from culture flasks. Homogenize the tissue or cells in 20 ml of 50 mM sodium potassium phosphate (pH 7.4, at 4° C.) with a Polytron (set at gear 6, 15 seconds). The homogenate was centrifuged at 48000 xg for 12 minutes at 4°C. The precipitate was resuspended in culture buffer (50mM sodium potassium phosphate, pH7.4, at room temperature, containing 0.1% bovine serum albumin) with Polytron (set at 6 gears, 15 seconds) to a concentration of 40 mg/ml and immediately added to Start the analysis in the test tube. The protein content of the crude membrane suspension can be determined by the method of OHLowery et al., J. Biol. Chem., 193 , 265 (1951).

Binding assays can be performed in duplicate in 12 x 75 mm polypropylene tubes in 50 mM potassium sodium phosphate (pH 7.4, at room temperature) containing 0.1% bovine serum albumin. The radioligand, [H ³ ]-mepyramine, was diluted to a concentration of 2 nM in incubation buffer and added to each tube (50 μl). Test compounds were diluted in incubation buffer (10 ^-10 M to 10 ^-5 M) and added to appropriate tubes (50 µl). Add 250 μl of well-mixed tissue suspension to start the analysis. The final culture volume was 0.5 ml. The analysis was performed at room temperature for 30 minutes. Add 3.5 ml of 0.9% sodium chloride solution (4°C) to end the incubation and filter through a GF/B funnel soaked overnight in 0.1% polyethyleneimine, using a Brandel cell trap. Filters were quickly washed twice with two 3.5 ml portions of incubation buffer and transferred to scintillation vials. Ecolume (9ml) was added to the vial. The vials were shaken and allowed to stand for 4 hours before being counted by liquid scintillation photometry. Specific binding was determined as the difference between tubes containing no test compound and tubes containing 10 [mu]M promethazine. The total membrane-bound radioactivity is usually about 5% of that added to the tube. Specific binding is typically 75%-90% of total binding as determined by the method of MD Debacker et al., Biochem. Biophys. Res. Commun., 197(3) , 1601 (1991).

The molar filterability of the compound that produces 50% inhibition of ligand binding at the screening dose is the _IC50 value expressed as the cumulative mean (±SEM) of n independent experiments.

Embodiment B intends to use antagonist to the antagonism of the iodized tachykinin combined with _NK1 receptor

One skilled in the art can determine the _NK1 receptor affinity of a proposed tachykinin antagonist by evaluation in guinea pig lung (Keystone Biologicals, Cleveland, OH). The tissue was homogenized with a Polytron in 15 volumes of 50 mM Tris-HCl buffer (pH 7.4, 4° C.) and centrifuged. The pellet was resuspended in Tris-HCl buffer and centrifuged; the pellet was washed twice by resuspension. The final pellet was resuspended in incubation buffer at a concentration of 40 mg/ml and kept at room temperature for at least 15 minutes before use.

Receptor binding was initiated by adding 250 μl of membrane preparation in duplicate to 0.1 nM of ¹²⁵ I-Bolton Hunter Lys-3 labeled substance P in a final volume of 500 μl of buffer containing 50 mM Tris-HCl (room temperature pH 7.4), 0.1% bovine serum albumin, 2 mM manganese chloride, 40 μg/ml bacitracin, 4 μg/ml each of leupeptin and chymostatin, 1 μM thiorphan and various doses of tachykinin antagonist. Incubate at room temperature for 90 minutes; add 50 mM Tris-HCl buffer (pH 7.4, 4° C.) to end the incubation and vacuum filter GF/B filters pre-soaked in 0.1% polyethyleneimine. Filter-bound radioactivity was quantified using a gamma counter. Non-specific binding was defined as binding in the presence of 1 μMP species.

Specific binding was calculated from total binding minus non-specific binding. The competition of the iodo P species for binding to the test compound or standard is expressed as a percentage of this maximum competition. _IC50 values (concentration required to inhibit 50% of receptor binding) for each test compound were generated by nonlinear regression with iterative curve fitting (GraphPAD Inplot, San Diego, CA).

Example C Histamine (H ₁ ) Antagonism in Guinea Pig Ileum

One skilled in the art can confirm that the compounds of the present invention are _H1 receptor antagonists in vivo by evaluating the ability of the compounds to inhibit histamine-mediated smooth muscle contraction. Male Hartlev guinea pigs weighing 200-450 grams were sacrificed by carbon dioxide inhalation. A section of ileum approximately 20 cm long was removed and cut into 2 cm segments. Each segment of ileum was placed in an organ bath at 37°C containing Tyrode's solution with constant 95% O ₂ /5% CO ₂ . The composition of Tyrode's solution is as follows: sodium chloride 136.9 mM, potassium chloride 2.68 nM, calcium chloride 1.8 mM, sodium dihydrogen phosphate 0.42 mM, sodium bicarbonate 11.9 mM and glucose 5.55 mM. Concentrations were measured with an isometric transducer (Grass FTO3C) and recorded on a multi-channel recorder and/or computer. Experiments were initiated after loading ileal strips with 1.0 g tension and allowing them to equilibrate for at least 30 min. Tissues were pre-incubated with vehicle or various concentrations of test compounds and then challenged with histamine.

Competitive H ₁ receptor antagonists caused a parallel shift of the dose-response curve of histamine to the right, and the maximum response did not fall back.

The potency of antagonism was determined by the magnitude of the shift and expressed as the _pA2 value, which is the negative logarithm of the molar concentration of antagonist that shifts the dose-response curve twofold to the right. The _pA2 value can be calculated using Schild analysis. O. Arunlakshana and HOSchild, Br. J. Pharmacol Chemother., 14, 48-58 (1958). When the slope of the line obtained by Schild analysis is not significantly different from (1), the compound acts like a competitive antagonist.

Embodiment D intends to use antagonist to the antagonism of the phosphatidylinositol conversion induced by tachykinin in vivo

Those skilled in the art can determine _NK1 receptor antagonism by measuring the accumulation of substance P-induced phosphatidylinositol (PI, phosphoinositides) in UC11 cells in the presence or absence of _NK1 receptor antagonists. Two or three days before analysis, cells were seeded on 24-well culture plates at 125,000 cells/well. 20-24 hours before analysis, cells were loaded with 0.5 ml 0.2 μM myo-[2-H(N)]inositol (American Radiolabeled Chemicals Inc., specific activity; 20 μCi/mmol). Cultured cells were maintained at 37 °C and 5% _CO2 environment.

On the day of analysis, aspirate the medium and culture the cells in RPMI-1640 medium containing 40 μg/ml bacitracin, 4 μg/ml each of leupeptin and chymostatin, 0.1% bovine serum albumin , 10 μM thiorphan and 10 mM lithium chloride. After 15 minutes, 0.1 ml of test compound was added to the cells. After another 15 minutes, different concentrations of substance P were added to the UC11 cells to initiate the reaction, and then incubated at 37° C., 5% CO ₂ for 60 minutes, with a final volume of 1 ml. To terminate the reaction, the medium was aspirated and methanol (0.1 ml) was added to each well. Two aliquots of methanol (0.5 ml) were added to the culture wells to collect the cells into chloroform resistant tubes. Chloroform (1 ml) was added to each test tube, followed by double distilled water (0.5 ml). Samples were vortexed for 15 seconds and centrifuged at 1700 xg for 10 minutes. An aliquot (0.9ml) of the aqueous phase (top layer) was removed and double distilled water (2ml) was added. The mixture was vortexed and loaded onto a 50% Bio-Rad AG1-X8 (formate, 100-200 mesh) exchange column (Bio-Rad Laboratories, Hercules, CA). The column was eluted sequentially with the following eluents: 1) 10 ml double distilled water, 2) 5 ml 5 mM disodium tetraborate/60 mM sodium formate, and 3) 2 ml 1 M ammonium formate/0.1 M formic acid. The third eluate was collected and counted in 9 ml of scintillation fluid. A 50 [mu]l aliquot of the organic phase (bottom) was removed, dried in scintillation vials and counted in 7 ml of scintillation fluid.

The ratio of DPM (total phosphoinositol) in each aqueous phase to 50 μl of DPM (total bound [ ^3H ]inositol) in each organic phase was calculated for each sample. Data are expressed as agonist-induced [ ³ H]-inositol phosphate accumulation as a percentage of basal levels. This ratio in the presence of the test compound and/or standard is compared to the ratio of a control sample (ie, no stimulating agonist).

Dose-response graphs are prepared and the ability of test compounds to inhibit tachykinin-induced turnover of phosphatidylinositol is determined with the aid of a computer program. Data represent total inositol phosphate accumulation as a percent of basal levels stimulated and corrected for the maximal response to substance P. Schild analysis using a dose-response curve, the value obtained represents the strength of the competitive antagonist, expressed in _pA2 , _pA2 is the negative logarithm of the molar concentration of antagonist that reduces the effect of a given dose of agonist to half the expected effect . The slope of the line obtained by Schild analysis was not significantly different from (1), and the compound acted like a competitive antagonist.

Example E Evaluation of H ₁ (or NK ₁ ) Antagonism in Vivo

Those skilled in the art can confirm that the compound of the present invention mediates anaphylaxis in vivo by evaluating the ability of the compound to inhibit the formation of guinea pig wheal induced by histamine (or substance P). Animals were anesthetized with pentobarbital (ip). The dorsal skin is shaved and histamine (or Substance P) is injected subcutaneously on the shaved surface at an appropriate time after application of the test compound. Dosage, route and timing of administration may vary according to experimental design. The design of such experiments is well known in the art. Immediately after the subcutaneous challenge, the animals were injected intravenously with 1% Evan's blue dye to visualize the wheals. Animals were sacrificed by _CO2 inhalation at an appropriate time after the animal was challenged. The skin was removed and the diameter of each wheal was measured in two perpendicular directions.

Wheal response was used as an index of edema response. Percent inhibition of wheal response was calculated by comparing drug-treated and vehicle-treated groups. The dose-response inhibition curve was linearly regressed to determine the ED ₅₀ value expressed in mg/kg. ED ₅₀ is the dose of the compound that inhibits the skin wheal induced by histamine by 50%.

Example F Evaluation of _NK1 Antagonism in Vivo

Those skilled in the art can determine that the compound of the present invention is an _NK1 receptor antagonist in vivo by evaluating the ability of the compound to inhibit substance P-induced plasma protein extravasation in guinea pig trachea. Leakage of substance P-induced proteins through postcapillary venules was estimated by measuring the accumulation of Evans blue dye in guinea pig trachea.

When the intended antagonist is administered intravenously, the animals are anesthetized with pentobarbital, followed by injection of Evans blue dye (20 mg/kg, intravenously, prepared in 0.9% sodium chloride solution). One minute after dye injection, the antagonist was administered iv, followed by substance P (0.3 nmol/kg, iv), and 5 minutes later, excess dye was removed from the circulation by transcardial perfusion with 50 ml of 0.9% sodium chloride solution. The trachea and major bronchi were removed, the blot dried and weighed.

When the intended agent is administered orally, the animals are anesthetized with pentobarbital and injected with Evans blue dye (20 mg/kg, iv, prepared in 0.9% sodium chloride solution) 1 hour after dosing. One minute after dye injection, substance P (0.3 nmol/kg, iv) was administered intravenously, and 5 minutes later, excess dye was removed from the circulation by transcardial perfusion with 50 ml of 0.9% sodium chloride solution. The trachea and major bronchi were removed, the blot dried and weighed.

The dye (620 nm) was quantified spectrophotometrically after leaching the tissue in formamide for 24 hours at 50°C. This value was subtracted from the blank (dye only, no agonist). The _ED50 (dose of compound that inhibits substance P-induced plasma protein extravasation by 50%) was calculated from linear regression analysis.

Claims (22)

1. Compounds of the following formula Wherein R' is 1 to 3 substituents, each of which is independently selected from hydrogen, CF ₃ , -OCF ₃ and C ₁ -C ₆ alkoxy; R" is hydrogen or a group selected from the following:

Wherein R ₂₀ is selected from hydrogen, C ₁ -C ₄ alkyl and -CF ₃ ; Ar ₁ is a group selected from the following: in R ₁ is 1 to 3 substituents, each of which is independently selected from hydrogen, halogen, -CF ₃ , C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; R ₂ is 1 to 2 substituents, each of them independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; X ₁ and X ₂ such as A), B) or C ) as defined in one of the parts: A) X ₁ is hydrogen; _X is a group selected from the following: in p is 1 or 2; R ₃ is 1 to 3 substituents, each of which is independently selected from hydrogen, halogen, -CF ₃ , C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; R ₄ is 1 to 3 substituents, each of which is independently selected from hydrogen, halogen, -CF ₃ , C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; _R is hydrogen or hydroxyl; _Ar is a group selected from the group consisting of:

in R ₆ is 1 to 3 substituents, each of which is independently selected from hydrogen, halogen, -CF ₃ , C ₁ -C ₆ Alkyl, C ₁ -C ₆ alkoxy and -CO ₂ R ₉ , wherein R ₉ is selected from hydrogen and C ₁ -C ₄ alkyl; R ₇ is 1 to 2 substituents, each of which is independently selected from hydrogen, halogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy; R ₈ is selected from hydrogen, -CH ₃ and -CH ₂ OH; R ₁₀ is selected from hydrogen, C ₁ -C ₄ alkyl and benzyl; Z is selected from hydrogen, C ₁ -C ₆ alkyl, -(CH ₂ ) _w -O-(CH ₂ ) _t -Y, -(CH ₂ ) _f A, -(CH ₂ ) _u CO ₂ R ₁₁ , -(CH ₂ ) _u C(O)NR ₁₂ R ₁₃ , -(CH ₂ ) _q C(O)(CH ₂ ) _h CH ₃ , - (CH ₂ ) _w' -O-Ar ₃ , -CH ₂ CH ₂ OCF ₃ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CH ₂ CF ₃ , -(CH ₂ ) ₂ CH=CH ₂ , -CH ₂ CH=CH ₂ , -CH ₂ CH=CHCH ₃ , -CH ₂ CH=CHCH ₂ CH ₃ , -CH ₂ CH=C(CH ₃ ) ₂ and -CH ₂ OCH ₂ CH ₂ Si(CH ₃ ) ₃ in w is an integer from 2 to 5; t is an integer from 1 to 3; f is 2 or 3; u is an integer from 1 to 4; g is an integer from 1 to 3; h is an integer from 0 to 3; w' is an integer from 2 to 4; Y is selected from hydrogen, -CF ₃ , -CH=CH ₂ , -CH=C(CH ₃ ) ₂ and -CO ₂ R ₁₄ , wherein R ₁₄ is selected from hydrogen and C ₁ -C ₄ alkyl; A is selected from -NR ₁₅ R ₁₆ , acetamido and morpholino, wherein R ₁₅ is selected from hydrogen and C ₁ -C ₄ alkyl and R ₁₆ is C ₁ - C ₄ alkyl; R ₁₁ is selected from hydrogen and C ₁ -C ₄ alkyl; R ₁₂ is selected from hydrogen, C ₁ -C ₄ alkyl and benzyl; R ₁₃ is selected from hydrogen and C ₁ -C ₄ alkyl; Ar ₃ is a group selected from the group consisting of:

in v is an integer from 1 to 3; R ₁₇ is selected from hydrogen and -CO ₂ R ₁₈ , wherein R ₁₈ is selected from hydrogen and C ₁ -C ₄ alkyl; B) X ₁ is hydroxyl; _X is a group selected from the following:

Wherein p, R ₃ , Z and Ar ₃ are defined as before; C) X ₂ is a group of the following formula: Wherein R ₃ and R ₄ are as defined above; and _X1 and _Z1 together form another bond between the carbon atoms bearing the _X1 and _Z1 groups; stereoisomers and pharmaceutically acceptable salts thereof. 2. The compound of claim 1, wherein _X1 is hydrogen. 3. The compound of claim 2, wherein _X is a group of the formula: wherein R ₃ , Ar ₂ and p are as defined in claim 1 . 4. The compound of claim 3, wherein _R3 is hydrogen, p is 1 and _Ar2 is 4-fluorophenyl. 5. The compound of claim 3, wherein _R3 is hydrogen, p is 1 and _Ar2 is pyridin-2-yl. 6. The compound of claim 3, wherein _R3 is hydrogen, p is 1 and _Ar2 is furan-2-yl. 7. The compound of claim 3, wherein _R3 is hydrogen, p is 1 and _Ar2 is furan-3-yl. 8. The compound of claim 2, wherein _X is a group of the formula: wherein _R and Z are as defined in claim 1. 9. The compound of claim 8, wherein Z is -( _CH2 ) _w -O-( _CH2 ) _t -Y, wherein w, t and Y are as defined in claim 1 . 10. The compound of claim 9, wherein w is 2. 11. The compound of claim 10, wherein Z is 2-ethoxyethyl. 12. The compound of claim 1, wherein _X1 is hydroxyl. 13. The compound of claim 12, wherein _X is a group of the formula:

wherein R ₃ , Ar ₂ and p are as defined in claim 1 . 14. The compound of claim 13, wherein _R3 is hydrogen, p is 1 and _Ar2 is 4-fluorophenyl. 15. The compound of claim 1, wherein the compound is (+)- or (-)-N-methyl-N-(4-(4-(1-(pyridin-2-ylmethyl)-1H-benzo imidazole-2-carbonyl)piperidin-1-yl)-2-(4-fluorophenyl)butyl)-3,4,5-trimethoxybenzamide or mixtures thereof. 16. The compound of claim 1, wherein the compound is (+)- or (-)-N-methyl-N-(4-(4-(1-(4-fluorobenzyl)-1H-benzimidazole- 2-carbonyl)piperidin-1-yl)-2-(3,4-dichlorophenyl)butyl)benzamide or mixtures thereof. 17. A pharmaceutical composition comprising the compound of claim 1. 18. A pharmaceutical composition comprising a compound of claim 1 in admixture or in combination with one or more inert carriers. 19. The use of the compound of claim 1, selectively combined with a pharmaceutical carrier, for the preparation of a pharmaceutical composition for treating allergic rhinitis. 20. The use of the compound of claim 1, selectively combined with a pharmaceutical carrier, for the preparation of a pharmaceutical composition for treating asthma. 21. The use of the compound of claim 1, optionally combined with a pharmaceutical carrier, for the preparation of a pharmaceutical composition for treating emesis. 22. The use of the compound of claim 1, selectively combined with a pharmaceutical carrier, for the preparation of a pharmaceutical composition for treating inflammatory bowel disease.